Cell Biology of Disease and Exercise Create account or Sign in

Search this site Search

Welcome page
Cystic Fibrosis Exercise
What is a Wiki Site?
How to edit pages? I. Introduction
How to join this site?
Cystic fibrosis (CF) is an inherited disorder that impacts multiple body systems, although primarily the pulmonary and digestive systems are
Site members affected.[1],[2] These implications are due to a defect in the cystic fibrosis transmembrane conductance regulator gene,[3],[4],[5] resulting in a
decreased life expectancy.[2] The benefits of exercise for those with CF have been shown at the functional level including improved pulmonary
Recent changes function,[6] increased sputum expectoration,[7] and significantly lower risk of death.[8] Although still in its infancy stages, this page will address the
List all pages emerging evidence of proposed cellular mechanisms that supports exercise as medicine for people with CF [9],[10] and the limited available
exercise recommendations for this population.
Page Tags

Site Manager
Fold
TOPICS Table of Contents
AGING Cell Bio I. Introduction
a. AGING Exercise II. Ion Regulation in the Lungs During Exercise
BREAST CANCER Cell Bio A. Nasal Transepithelial Potential Difference
a. Breast Cancer Exercise 1. Determining Nasal Potential Difference During Exercise
METABOLIC SYNDROME Cell Bio 2. Effects of Exercise on the Transepithelial Potential Difference
a. Metabolic Syndrome Exercise Study 1
STROKE Cell Bio Study 2
a. Stroke Exercise Implications
MUSCULAR DYSTROPHY Cell Bio Recommendations
a. Muscular Dystrophy Exercise B. P2Y2
MULTIPLE SCLEROSIS Cell Bio Implications
a. Multiple Sclerosis Exercise C. Atrial Natriuretic Peptide
HIV/AIDS Cell Bio Implications
a. HIV/AIDS Exercise D. Arginine Vasopressin
Implications
Forum E. AMP-Activated Protein Kinase
Forum Implications
III. Ion Regulation in the Sweat Glands During Exercise
Recent posts Study 1
Study 2
Page tags Recommendations
IV. Exercise and Inflammatory Cytokines
A. IL-6 & TNF-
angiogenesis axis brca1 brca2 B. Precursors to IL-6 and TNF-
breast cancer catecholamines C. IL-10
Implications
cells central cortisol
Recommendations
cytokines duration
V. Exercise and Growth Factors
A. Growth Hormone & IGF-1
exercise fat glut-4 hpa Implications
inflammation insulin Recommendations
VI. Exercise and Bone Mineral Density
metabolic mitochondria VII. Exercise and Oxidative Stress
mrna obesity oxidative pai-1 Implications
peroxidation pgc1 prescription VIII. Sex related differences and Exercise
Implications
stress syndrome tnf-
Recommendations
IX. Conclusion and Recommendations for Exercise in People with CF
Add a new page Comments

new page

edit this panel

II. Ion Regulation in the Lungs During Exercise
A. Nasal Transepithelial Potential Difference
1. Determining Nasal Potential Difference During Exercise

Ions, such as sodium (Na+) and chloride (Cl-), moving into and out of the cell create a nasal transepithelial potential difference (TPD) in the airway
lining and the lumen and this potential difference can show the abundance of either Na+ or Cl- within the lumen.[11] Researchers measure the
nasal TPD by placing electrodes in the nasal cavity of the individual.[11] The nose lining is then exposed to a variety of solutions.[11][12] When the
solutions are added, they can predictably change the TPD in the airway lining, making it possible for researchers to determine the effects of
various ion exposure to the epithelial membrane in both normal subjects and subjects with CF.[11]

Figure 1: Nasal Potential Difference Testing in Normal Ion Regulation

Images taken from: http://www.hopkinscf.org/main/whatiscf/diag_testnasal.html

Normal ion regulation Amiloride added Cl- free solution added Isproterenol a

In a normal ASL lumen, the addition In the next stage, isopr

of amiloride, which blocks Na+ In normal subjects, when a Cl--free added to the lumen. Iso
The nasal TPD in a healthy person's
airway lumen is more positive (less
transport into the cell, causes the solution (isotonic) is added to the stimulates Cl- secretion
lumen of the lung to become more lumen, the cells increase the K-dependent pathway t
negative) than that of a patient with
positive.[11]. The inhibition of Na+ secretion of Cl- into the lumen via the CFTR.[11] Isoproterent
 CF because the Na+ reabsorption is
better controlled and Na+ remains
outside the cell to balance the Cl-
concentration.[11] There is adequate
ion regulation of both Na+ and Cl- into
and out of the cell during
homeostasis.[11]
causes a decrease in the Cl-
absorption into the cell to compensate
for this increase in positive charge in
the lumen (outside the cell).[11] This
decreases the TPD with the cell
membrane potential becoming less
negative in response to the increase
in Na+ ions in the lumen.[11][12]
CFTR channels that stimulate the
efflux of Cl- out of the cell.[11] This
increases the salt (NaCl)
concentration in the lumen, which
improves the airway surface liquid
(ASL) volume because water follows
NaCl.[11]
synthetic catecholamin
stimulates the beta 1 an
adrenergic receptors to
activate CFTR.[11][13]
in Cl- efflux and secreti
lumen makes the nasal
negative as Cl- ions are
the lumen.[11]

Figure 2: Nasal Potential Difference Testing in CF

Images taken from: http://www.hopkinscf.org/main/whatiscf/diag_testnasal.html

CF Ion Regulation Amiloride Added Cl- free solution added Isproterenol a

When amiloride is added to the

Baseline nasal potential for
individuals with CF, the nasal TPD is
typically much lower (more negative)
than healthy subjects due to the
uninhibited Na+ reabsorption.[11]
lumen, there is a rapid increase in the
Na+ present in the lumen due to the
inhibition of the Na+ transport back
into the cell.[11] This decreases the
TPD as the lumen becomes more
positive.[11] Because CFTR is
defective, there is only minimal
transport of Cl- via other channels.[11]
As a result of Na+ reabsorption
inhibition, there is an increase in the
NaCl content of the lumen. Because
water follows solutes, there is an
increased ASL volume.[11]
Addition of the Cl--free solution
causes little change in the TPD as
there is very little Cl- that can be
secreted out of the cell into the lumen
secondary to a defective CFTR.[11]
Once again, the additio
synthetic catecholamin
(isproterenol), which wo
trigger a Cl- efflux via th
mediated pathway, is b
there is minimal secreti
the cell into the lumen h
little change in the TPD

By comparing nasal TPD testing in normal and CF patients during homeostasis, researchers can determine the channels, proteins, and other
components influenced during exercise and the effect of different exercise types on the nasal TPD.

2. Effects of Exercise on the Transepithelial Potential Difference

Study 1

Reference:Hebestreit et al., 2001[12]

Type of Study:Controlled Clinical Trial
Subjects: 9 healthy subjects (controls aged 15-33 years old) 9 subjects with CF (aged 10-31 years old)[12]
Exercise Intervention: Subjects were tested during 2 sessions with less than 14 days between sessions[12]

1. Maximum power cycling: One session included cycling to volitional fatigue on a cycle ergometer while supine with the head elevated 30
degrees. Power was raised every 2 minutes with subjects being instructed to pedal for at least 8 minutes. This session was only used to
determine moderate-intensity exercise for each participant. No nasal TPD readings were taken at this visit.[12]
2. Cycling at 85% of Ventilatory anaerobic threshold (VT): The second session involved subjects cycling on a cycle ergometer semi-supine
with the head elevated 30 degrees. The subjects pedaled for at least 10 minutes at 85% of their ventilatory thresholds[12]

Outcomes and Results:

1. Transepithelial nasal potential difference PD at rest and with exercise.[12]

At rest, the TPD was more negative in the control group than the group with CF.[12]
After 10 minutes of exercise at 85%, the TPD decreased (became less negative) in subjects with CF as compared to rest. Exercise
changes with regards to difference in TPD were significantly larger than the control group (p<0.001).[12]
No significant difference in nasal TPD between healthy controls and patients with CF after 10 minutes of exercise.[12]
2. Change in potential difference with the addition of amiloride (PDamil) at rest and during exercise[12]
PDamil was significantly less with exercise than at rest in both CF and healthy subjects.[12]
3. Change in potential difference with addition of Cl- solution and isoprotenerol (PDlow Cl/iso) at rest and during exercise[12]
There was little change in PDlow Cl/iso during exercise and rest in both the CF and healthy control group.[12]

Study 2

Reference:Schmitt et al., 2011[13]

Type of Study: Controlled clinical trial
Subjects:11 healthy subjects, 9 subjects with exercised induce asthma (EIA), 10 subjects with CF[13]
Exercise Intervention:Intervention included 2 sessions of exercise with at least 7 days in between each session[13]

1. Maximum exercise test: One session of cycling until volitional fatigue on a cycle ergometer lying down with the head elevated 30 degrees
initially at 50 W; power was increased by 25 W every 3 minutes. Nasal TPD was measured before exercise, immediately after exercise and
20 minutes later.[13]
2. Submaximal exercise: One session of cycling for 20 minutes on a cycle ergometer supine with the head elevated 30 degrees at a workload
rate determined from the maximum exercise test and below anaerobic threshold. Nasal TPD was measured before exercise, 15 minutes
into exercise, and 20 minutes after exercise.[13]

Outcomes and Results: Nasal TPD readings taken at rest, 15 minutes into exercise, immediately after exercise, and 20 minutes after exercise[13
]

1. Nasal potential total (NPtotal)[13]

In patients with CF, the NPtotal was more negative than the control and EIA group at rest.[13]
There was a decrease (became less negative) in NPtotal (~10mV) in patients with CF during BOTH maximal and submaximal
exercise which was significantly larger than the EIA or control group.[13]
Slight decrease was found with NPtotal in the control group with maximal exercise but not with submaximal exercise.[13]
After the 20-minute recovery each groups NPtotal returned to their baseline values[13]
There was no change in the NPtotal in the EIA group in either maximal or submaximal exercise.[13]
2. Nasal potential after amiloride solution (NPamil)[13]
 There was a decreased NPamil in patients with CF after maximal exercise (~10mV) but not in either the control or EIA group[13]
There was no significant change in NPamil during submaximal exercise in any groups.[13]
3. Nasal potential after low chloride plus isoproterenol (NPCl-)[13]
There was a lower NPCl- in the CF group in all exercise conditions as compared to both controls and EIA[13]
4. Catecholamines (epinephrine and norepinephrine) and glucocorticoids (cortisol) in blood at rest, 15 minutes into exercise, and immediately
after maximal exercise[13]
Epinephrine was lower in CF after maximal exercise likely due to the decreased exercise intensity. No change between groups with
submaximal exercise.[13]
Norepinephrine was significantly lower in patients with CF and EIA compared to controls during maximal exercise, while there was no
change during submaximal exercise.[13]
Cortisol levels did not change between groups during any exercise conditions.[13]

Hebestreit et al. concluded that exercise may partially block Na+ reabsorption into cell with moderately intense exercise.[12] With exercise, the
change in nasal TPD in subjects with CF decreased, eluding to a more positively charged lumen (more Na+ present outside the cell).[12]
Additionally, the change in nasal TPD with addition of amiloride at rest and with exercise in subjects with CF was less than the healthy controls,
indicating that Na+ reabsorption was being inhibited prior to the addition of the amiloride in the healthy subjects but not the subjects with CF.[12] To
further prove that the Na+ channels were inhibited, there was no change in the nasal TPD at rest and with exercise in subjects with CF after the
addition of a solution low in Cl- and with isoprotenerol.[12] This shows that the Cl- was still present in the lumen and the addition of the solutions
did not alter the ion regulation in the lung epithelial tissue. One possible mechanism for this was that exercise and mechanical stress via increase
in ventilation rate can trigger the release of ATP which has been previously shown and speculated to inhibit Na+ channels.[12]

In the study by Schmitt et al., because there was no change in the nasal TPD or NPamil until after maximum exercise in the healthy controls, one
can speculate that nasal TPD may depend on exercise intensity.[13] In patients with CF, the changes in the nasal TPD were smaller than those
reported by Hebestreit et al. after submaximal exercise; however, there was still a decrease in the TPD (lumen became more positive). Larger
changes in the nasal TPD for subjects with CF occurred only at a submaximal exercise intensity; whereas in the healthy controls, there was no
change until after maximal exercise.[13] Therefore, the inhibition of Na+ reabsorption may depend on exercise intensity with Na+ reabsorption still
being inhibited with submaximal exercise in patients with CF.[13] Additionally, catecholamine levels were not affected by exercise.[13]

Implications
It is important to understand the limitations with both of these studies. One limitation includes that subjects in both studies performed only short
exercise bouts for 2 sessions. Therefore, the effects of chronic exercise on the nasal TPD are unknown at this time. One can speculate that while
the nasal TPD is positively affected with exercise, the effects may not be sustained as nasal TPD levels returned close to baseline after 20 minutes
of rest in the Schmitt et al. study.[13] Consequently, exercises ability to inhibit Na+ reabsorption and promote Cl- secretion may be only a transient
change. Additionally, the only exercise intervention studied was cycling in a semi-supine position so other exercise interventions should be
considered. Areas for further research include the use of animal models to test the effects of chronic exercise at varying intensities to determine if
there is a long term effect on the nasal TPD.

Recommendations
In patients with CF, while the aforementioned studies had limitations, the results have large implications on the effects of exercise. Patients with CF
can perform submaximal exercise and actually change the TPD in their airway lumen in a beneficial way. Because exercising, specifically cycling,
at a submaximal level decreased Na+ reabsorption, it is recommended that this type of activity be performed by patients with CF to increase their
ASL volume and decrease the chance of infection.

B. P2Y2
Two reviews suggest that exercise is beneficial in CF at the cellular level through the activation of the purinergic (P2Y2) pathways that help control
the ion channels in sweat glands and epithelial cells in the airways.[9],[10] As stated in the cell biology section, P2Y2 is activated by ATP and its
metabolite adenosine (ADO).[9] The activation of P2Y2, receptors by ATP and ADO cause a depletion in phosphatidylinositol 4, 5-biphospate
(PIP2).[9] This indirectly inhibits ENaC (and thus, Na+ reabsorption) because PIP2 is needed for activation of ENaC by protein kinase C.[9] The
depletion in PIP2 results in the formation of inositol triphosphate (IP3) and diacylglycerol (DAG) with IP3 going on to mediate the release of Ca2+
from the endoplasmic reticulum.[9] This Ca2+ can then activate the calcium dependent chloride channels (CaCC), allowing for the secretion of Cl-.[
14] The inhibition of ENaC and the activation of CaCC promotes an increase in ASL by blocking Na+ reabsorption and increasing Cl- secretion.[14]

ATP has been shown to be released with the exposure to physical forces from several factors, including mechanical deformation,[15],[16],[17],[18]
stretch,[19],[20] shear stress from fluid,[21],[22],[23],[24] and osmotic shock.[25],[26][27] Mechanical deformation is the most important mechanism
of ATP release for the exercise section because ventilation imparts a phasic shear stress in the airway, influencing the activation and inhibition of
mechanosensitive channels that regulate ions within the cells.[27] Possible mechanisms that activate these channels in response to mechanical
stress include changes in the shape of the lipid bilayer, phosphorylation or dephosphorylation of signaling proteins, and changes in the strain of the
cytosol; however, the exact mechanism is unknown.[27] Because of the increase in tidal volume and respiratory rate that occur with exercise,
exercise may improve pulmonary function in individuals with CF through ATP release and subsequent P2Y2 activation and improved ion regulation.
[10] Thus, the inhibition of Na+ in the nasal passage reported by Hebestreit et al.[12] may be the result of the increase in ATP released from
increased ventilation during exercise. Although Hebestreit et al.[12] did not link the increased ATP to activation of P2Y2, a study by Tarran et al.[24]
performed a few years later provides in vitro evidence regarding this relationship to pericilliary layer (PCL) volume. Before discussing the influence
of ATP on PCL volume, it is important to note that Donaldson et al.[28] found a similar concentration and release rate of ATP in both normal and CF
airway epithelial cells in vivo. Consequently, it is important to review the literature in regards to the effects of mechanical stress on ATP and ion
regulation.

As mentioned in the cell biology section, maintaining ASL hydration is important for pulmonary function.[29] In normal cells, ASL is maintained by
adequate Cl- secretion and Na+ reabsorption to regulate the PCL.[24] However, in CF, the PCL isn't properly regulated because of lack of CFTR.[
24] Therefore, because P2Y2 participates in ion regulation through an increase in Cl- secretion and decrease in Na+ reabsorption, its influence on
ASL height has been studied.[24] This is important when assessing the effects of exercise in CF because improvement in ASL height, specifically
the PCL, is beneficial for the innate immune system of the lungs.[27]

Tarran et al. conducted several in vitro experiments to determine the effect of mechanical shear stress, specifically phasic shear stress, on the
volume of the PCL in normal and CF epithelial cells.[24] The authors cultured airway epithelial cells from the bronchial specimens of 15 normal
subjects (6 females and 9 males) and 21 subjects with CF (9 females and 12 males).[24] A new incubator was developed to create a phasic shear
stress to simulate the shear stress induced by breathing in humans with the frequency and magnitude of the shear stress and motion being
controlled by a series of devices.[24]

The authors experiments and results are summarized below:

In response to phasic shear stress, the authors found that both normal and CF airway epithelial cells responded similarly by reaching a
"normal" height (7 micrometers) for PCL volume.[24] This is a very important finding demonstrating that motion can trigger signals that
cause PCL volume to reach an effective height for the cilia to beat and clear bacteria from the mucus layer.[24]

When looking at the effect of ATP concentration on PCL homeostasis, the authors first analyzed if there was a positive relationship between
the amount of shear stress and ATP released to provide a corresponding increase in PCL volume.[24] They found that PCL volume in a
static environment was indeed related to the amount of shear force.[24] Additionally, the authors found that the increase in PCL volume in
CF airway epithelial cells in response to phasic shear stress was regulated solely by ATP, which differed from the PCL volume in normal
airway cells that was also influenced by adenosine.[24]

The authors were then interested in the link between ion transport and the release of ATP from phasic shear stress.[24] The CF cultures
were put in a chamber that measured intracellular Ca2+ and Cl- secretion, a measure found to assess the ATP signaling pathway in the
epithelial cells of airways,[30] while phasic shearing forces were intermittently applied.[24] The phasic shearing increased Cl- secretion
(leading to increased TPD) and Ca2+ concentration.[24] Amylase, an enzyme that degrades ATP to AMP, was then added to differentiate
 the pathway involved in the Cl- secretion.[24] Because the effect of the phasic shear stress on Cl- and Ca2+ disappeared with application of
this enzyme, the authors considered this strong evidence that changes in phasic shear stress activate ATP release that specifically
influence P2Y2 receptors.[24]

The final inquiry the authors addressed was the increased incidence of chronic lung infections in patients with CF despite normal tidal
volume influencing the release of ATP to appropriately regulate the PCL.[24] It was found that the CF cultures infected with respiratory
syncitial virus (RSV) and exposed to phasic shear stress (equivalent to normal tidal breathing in vivo) resulted in a reduction in PCL to ~4.5
micrometers, which is inadequate to provide mucus transport.[24] Additionally, the authors previously found that inflammation causes an
increase in extraceullar ATPase, which lowers ATP concentration in PCL.[24] Therefore, normal tidal breathing is unable to maintain the
PCL volume in infected CF airways.[24] The data in this experiment showed that the upregulation in enzymes that degrade ATP was the
result of the actual RSV versus the release of cytokines to fight the infection because CF cultures were able to maintain PCL height with
cytokine exposure but not RSV.[24]

Figure 2: ASL Height in CF and Normal Airway Epithelial Cells[24]

http://www.jbc.org/content/280/42/35751/F7.large.jpg

Implications
These in vitro results provide evidence of the possible mechanisms behind improved lung
function that has been associated with exercise.[6],[31],[32],[33],[34],[35] This study
suggests that the increased ventilation with exercise may provide the mechanical stimulus
(phasic shear stress) to release ATP. This ATP goes on to activate P2Y2 which promotes Cl-
secretion and Na+ reabsorption to increase PCL height, aiding in the ciliary function to keep
the lungs free of infection.[24] The effects of phasic shear stress on PCL volume in normal
and CF airway epithelial cells are summarized in Figure 2 above by Tarran et al.[24] The
results of this in vitro study need to be analyzed in animal models to assess the effects of
exercise on ATP release, P2Y2 activation, ASL volume, and pulmonary function. Specifically,
the effects of increased ventilation during exercise on PCL volume in animal models infected
with pulmonary diseases, like RSV, should be investigated to determine if the increased
phasic shear stress can maintain PCL volume despite the decrease in ATP found with this
virus. It is crucial that these effects of exercise begin to be studied in animal models as a
starting point in determining the specific benefits and detrimental effects that occur as the
result of aerobic exercise. These findings can then be applied to humans to determine the
ideal frequency, intensity, and duration to optimize the positive benefits of aerobic exercise
in individuals with CF.

C. Atrial Natriuretic Peptide

This critical analysis of atrial natriuretic peptide (ANP), a polypeptide hormone, is reserved for the exercise page because ANP is secreted by the
heart in response to atrial stretch from increased blood pressure and volume,[36],[37],[38] which occurs during exercise.[10] A recent review by
Cholewa et al. suggests that the increased release of ANP during exercise may be another benefit of exercise in individuals with CF.[10] This
theory is based on studies that have shown an inhibition of Na+ reabsorption in respiratory epithelial cells of murines and rats without CF following
circulation of ANP in the lungs.[39],[40]. Like Cholewa et al., Hebestreit et al. theorized that ANP may be partially responsible for the observed
decrease in Na+ reabsorption in the airway epithelial cells after exercise, resulting in a decreased TPD.[12] Once again, a decreased TPD has
been associated with increased Cl- secretion and improved ASL hydration.[10] Although the study by Hebestreit et al. [12] analyzed TPD in
subjects with CF, the effects of ANP have not been analyzed in CF tissues. Therefore, the proposed benefits of ANP on CF tissue is based on the
cell mechanisms observed in normal tissue and the underlying pathophysiology observed in CF.

ANP synthesis and activity has been found in the heart,[41] brain,[42],[43] lung,[44] and pulmonary and systemic vasculature.[41],[45] When
secreted, ANP binds to a natriuretic peptide receptor (NPR) like NPR-A, a protein included in the membrane guanylyl cyclase family.[41][46] ANP
binding to NPR-A activates cyclic guanosine 3',5' monophosphate (cGMP).[41],[47],[48]. Cyclic GMP has been shown to inhibit Na+ channels[39]
While the evidence for inhibition of Na+ reabsorption is well documented after ANP perfusion,[24],[36],[39],[40] there are gaps in the literature
related to the exact mechanism of ANP-induced inhibition of Na+ reabsorption. One study by Novaira et al.[36] demonstrated increased mRNA
coding CFTR expression in the proximal colon of rats after exposure to ANP, suggesting that ANP contributes to the amount of CFTR expressed in
the epithelial cells of the intestines.[36] Moreover, these authors refer to the possibility that ANP inhibits Na+ reabsorption through cGMP-
dependent protein kinase G signaling cascades [49] that activate CFTR,[50], inducing Cl- secretion and Na+ inhibition.[36] Although the study by
Novaira et al. provides evidence for the influence of ANP on CFTR, it does not analyze the effects of ANP on other mechanism that influence Na+
regulation. In regards to additional methods of inhibition of Na+ reabsorption, a study by Campbell et al. found that ANP decreased the Na+/K+
ATPase pump in vitro in alveolar epithelial cells of rats.[51] Cholewa et al. infers that inhibition of this pump will lead to a decrease in the
electrochemical force driving Na+ into the cell,[10] providing an alternate method for decreased Na+ reabsorption that is much more applicable to
CF tissue in which Na+ reabsorption cannot be inhibited by CFTR activation.

Exercise has been found to mediate a neuroendocrine response in an intensity-dependent relationship with the majority of hormones increasing
with an increase in exercise intensity.[52] The hypothalamic-pituitary-adrenal-axis is activated during exercise with the pituitary gland releasing
peptide hormones and the adrenal glands secreting catecholamines and corticosteroids.[10] In addition to secretion by the pituitary gland, ANP has
been found to be released by the heart during an increase in blood volume or blood pressure, which occurs during exercise.[53] Furthermore, ANP
has been reported to increase during short-term, high-intensity exercise and prolonged aerobic exercise.[53],[54],[55],[56] A study by Mandroukas
et al., with a repeated measures design, found that ANP increased significantly after submaximal and maximal cycling in 10 healthy females with
the average age of 20.5 years.[55] The exercise protocol included submaximal cycling at 100 W (40-50% maximal heart rate) for 20 minutes
followed by a period of maximal exercise achieved by an increase of 25 W each minute until the individual reached exhaustion.[55] ANP levels
were positively correlated to exercise intensity and duration with an increase from an average of 49 pg/ml at rest to an average peak level of
95.7 pg/ml during maximal exercise.[55] The authors also found that the ANP levels were significantly reduced (average of 80 pg/ml) after 10
minutes of rest, suggesting that the heart stops secreting ANP during rest.[55]

A later study by Mandroukas et al., with a cross-over, repeated measures design, confirmed these results in males by testing the influence of four
different exercise running protocols (maximal test, continuous running for 32 minutes at 12 km/hr, alternating every 4 minutes between running at
12 km/hr to 8 km/hr for 32 minutes, and alternating every 4 minutes between running at 12 k/hr and resting) on ANP in 15 healthy, moderately-
trained trained men with an average age of 22.3 years.[56] The authors found the greatest increase in ANP occurred during the bout of maximal
exercise with an improvement from an average of 44.8 pg/ml at rest to an average of 102.3 pg/ml during maximal exercise.[56] Continuous running
also resulted in an increase in ANP from an average of 44.8 pg/ml to an average of 63.3 pg/ml after 32 minutes.[56] The authors reported a
decrease in ANP from baseline during the running protocols that required only intermittent running at 12 km/hr.[56] ANP levels returned to near
baseline after all four exercise protocols.[56] The authors concluded that the intensity of exercise is more important than the duration to increase
ANP release, with short-term high intensity exercise having the greatest effect.[56] Weaknesses in these studies include lack of a control group,
long-term outcome measures, and of the use of both male and female subjects. Additionally, these studies only analyzed ANP after a single bout of
exercise and the subjects were moderately-trained. Therefore, it is difficult to make generalizations to other populations, including individuals with
CF. However, one can hypothesize that the secretion of this hormone would be similar because CFTR dysfunction does not appear to affect
hormones released from the heart.

Implications

Although the influence of ANP on the inhibition of Na+ reabsorption has been researched in animal models without CF to determine the effects of
ANP on Na+ regulation,[40],[51] it is difficult to translate these results to CF tissue because the exact mechanism of ANP-induced inhibition of Na+
inhibition is not known in non-CF tissue. Therefore, more studies are needed to determine the exact mechanism that allows ANP to provoke Na+
reabsorption in epithelial tissue. Specifically, the influence of cGMP on P2Y2 should be assessed to determine if this alternate pathway for inhibition
of Na+ reabsorption, especially beneficial in CF, is activated. Moreover, studies are needed to determine the effects of ANP during exercise in vivo.
Because there is too much Na+ reabsorption occurring in CF cells, increased ANP from exercise may assist to inhibit Na+ reabsorption, leading to
a decrease in the TPD and an increase in the drive for Cl- secretion.[10] Based on the limited studies by Mandroukas et al., short-term maximal
intensity will have the greatest benefit in increasing the circulating levels of ANP.[56] More studies are warranted to determine the effects of ANP
on CF tissue to assess if exercise induces benefits related to this hormone in patients with CF.

D. Arginine Vasopressin
Arginine Vasopressin (AVP) is a hormone produced by the posterior pituitary gland as well as bronchial epithelial cells.[57] AVP has been proposed
to play a role in promoting airway hydration in patients with CF and exercise may contribute to greater production of this hormone.[10] However,
stronger research is needed at this time in order to fully understand its implications in CF and to make exercise recommendations.

Multiple factors such as reductions in plasma volume and plasma osmolality from exercise contribute to increases in plasma AVP concentrations.[
58] Besides plasma levels of AVP, exercise contributes to a pathway that raises bronchial epithelial cell production of AVP. Progressive exercise
increases bradykinin and activates kallikrein. [57],[59],[60],[61] Plasma kallikrein then additionally increases bradykinin production which leads to
AVP release from bronchial epithelial cells.[57],[59],[60],[61] A study on physically active subjects with an average age of 27 years discovered
significant increases in bradykinin with 10-minute periods of dynamic plantar flexion contractions at different workloads and 10 minutes of rest
between each bout; however, there was no conclusive evidence about the ideal workload level.[59]

AVP affects ion regulation which may in turn reduce water absorption of the lumen in airway epithelial cells, but more research on the effect of AVP
on TPD in patients with CF is needed.[10] AVP binds to multiple receptors, and V1b is one example of an apical membrane receptor located in the
trachea and bronchi that is coupled with G-proteins.[10] After this AVP binding to V1b, phospholipase C is activated and causes PIP2 cleavage.[10]
PIP2 cleavage results in less Na+ absorption through ENaC inhibition as well as increased Cl- secretion through CaCC.[10] It has been suggested
that CaCC can be used to bypass the defective CFTR channel,[9] and these findings demonstrate that increased AVP may be a potential
mechanism for increased CaCC activation in patients with CF. Additional influences on increasing Cl- secretion result from influx of ions through
Na+-K+-ATPase pump and Na+/K+/2Cl- cotransporter due to binding of AVP on basolateral V2 receptors.[10] One study reported a reduction in
TPD and 17% increase in water flux from basolateral to luminal membrane in epithelial tracheal cells in response to administration of AVP.[62] In
addition to effects on TPD and Cl- secretion, Tamaoki et al.[63] found a significant increase in cilia beat frequency that occurred three minutes after
AVP administration and lasted for approximately 20 minutes in rabbit trachea epithelia. This increase in cilia beat frequency could contribute to
improved mucous clearance for patients with CF.[10]

Implications
The findings discussed above suggest mechanisms caused by AVP, such as ENaC inhibition and CaCC activation, that contribute to reduced
water absorption of the lumen.[10] This increased CaCC activation could also lead to a potential bypass system of dysfunctional CFTR in patients
with CF. [9],[10] Additionally, AVP can contribute to improved mucous clearance due to increased cilia beat frequency. Although there is evidence
linking progressive exercise to increased AVP release in typical bronchial epithelial cells,[57],[59],[60],[61], this has not yet been shown in patients
with CF. There is also insufficient research regarding exercise and its implications to make an exercise prescription based on this cell mechanism
for this patient population.

E. AMP-Activated Protein Kinase

It has been proposed that aerobic exercise promotes airway hydration, reduces oxidative stress, and reduces airway inflammation through 5
adenosine monophasphate-activated protein kinase (AMPK).[10] AMPK is an intracellular kinase that is activated under metabolic stress
conditions such as hypoxia or increased AMP:ATP ratios.[10] Actions of AMPK include pathway and transcriptional regulation.[64] Pathways that
utilize ATP are down regulated and pathways that make ATP are up regulated by AMPK activation.[64] A restoration in the cells energy stores is
the resulting net effect of AMPK.[65]

It has been found that total AMPK is greater in airway epithelial cells for people with CF compared to those without.[66] Additionally, increased
stretch in airway epithelia is a proposed mechanism which may activate AMPK.[65] After 15 minutes of increased mechanical ventilation, one study
demonstrated a significant increase in activation of AMPK in mice airway epithelial cells in vivo.[65] Cyclic stretch resulted in an almost 50%
increase of AMPK activation in in vitro alveolar epithelial cells.[65] This specific investigation showed the controlling effects of dystroglycan, a
scaffolding protein involved in mechanical deformation conduction,[67] on AMPK activation. When dystroglycan is inhibited, the activation of AMPK
was absent in alveolar epithelial cells and there was an increase in mitochondrial production of reactive oxygen species.[65] Therefore,
dystroglycan plays a role in AMPK activation through the laminin-dystroglycan-plectin complex.[10],[68] Mechanical deformation which may
increase activation of AMPK is induced through an increased depth of breathing that can be caused by exercise.[10], [27]

AMPK has numerous effects on ion regulation, specifically Na+ absorption, that may reduce TPD resulting in better airway hydration in those with
CF.[10] AMPK plays a role in inhibition of Na+-K+-ATPase through activation of protein kinase C.[69] Additionally, there is possible reduction of
apical Na+ absorption and basolateral Na secretion through direct AMPK inhibition of the basolateral Ca2+-activated K+ channel, which decreases
both the electrical and chemical gradients.[70] Reduced ENaC activity caused by inhibition of PIP2 binding and decreased apical membrane ENaC
quantity caused by diminished PIP2 binding are two main effects of AMPK that may reduce the TPD and have positive effects on airway hydration
in those with CF.[71] Although not yet shown in lung or airway epithelial cells, AMPK activation decreases radioactive oxygen species in cardiac,
endothelial, and liver epithelial cells which reduces oxidative stress.[72],[73],[74] Research has also shown activation of AMPK causes an inhibition
of specific pathways, such as factor kappaB, which in turn reduces cytokines and decreases inflammation in bronchial epithelial cells in people with
CF.[66],[75]

Although there is evidence supporting proposed AMPK activation benefits, more research is needed that involves conclusive effects of AMPK
activation in people with CF versus healthy epithelial tissue as well as a causal link between exercise interventions and AMPK activation. The
implications of increased AMPK activation at the organ level are also important to consider because a study has suggested a negative
consequence.[76]

Implications
AMPK may reduce TPD and promote airway hydration,[71], decreases ROS levels in specific healthy human tissues,[72],[73],[74], and has been
shown to reduce bronchial epithelial cell inflammation in patients with CF.[66],[75] Increased depth of breathing achieved through exercise could
activate AMPK through airway epithelia stretch [10],[27],[65] and patients with CF do have increased AMPK in airway epithelial cells.[66] However,
there is limited research available for exercise-induced AMPK implications in patients with CF.

III. Ion Regulation in the Sweat Glands During Exercise

As previously described in the cell bio portion, ion dysregulation also occurs in the sweat glands in patients with CF with a high concentration of
NaCl in the sweat. This gives way to the theory that both Na+ and Cl- are not absorbed in the sweat duct in patients in with CF.[77] In the sweat
ducts of healthy tissue, both CFTR and ENaC are on the apical membrane and have been proven to operate together to regulate ions in the sweat
glands.[77]Therefore, a dysregulation of CFTR can inhibit Na+ reabsorption and cause both Na+ and Cl- to be excreted out of the body, causing
salty sweat.[77] The following studies address the effects of exercise on the sweat glands in healthy subjects, subjects with salty sweat, and
subjects with CF.

Study 1

Reference:Brown et al., 2011[78]

Type of Study:Cross sectional research design
Subjects:6 normal sweaters, 6 very salty sweaters (SS), 6 subjects with CF
Exercise Intervention:Cycling in a heated environment at 50% of VO2 max; 20-minute bouts with 5-minute rest breaks; Cycling continued until
subject lost 3% of body weight via sweating.
Outcome Measures and Results:

1. Basal ALDO (aldosterone) and AVP (Vasopressin concentration)

No significant differences with ALDO between all groups; Basal AVP was higher in the group of SS compared to the control group;
CF group had no differences in basal AVP amongst all groups; higher Na+ concentration in sweat correlated to higher AVP in the
blood in patients without CF
2. Amount of CFTR and ENaC in membrane
 Decreased CFTR abundance in SS and CF as compared to controls; no significant difference in ENaC abundance across all groups
Decreased CFTR in duct correlated to increased concentrations of Na+ and Cl- in sweat in healthy controls only; in patients with CF,
the abundance of CFTR did not "significantly" affect the NaCl sweat concentration.
In patients with CF, there was a direct relationship between ENaC in lumen and concentration of Cl- in the sweat

Study 2

Reference:Brown, Haack, et al., 2011[77]

Type of Study:Cross sectional research design
Subjects:8 very salty sweaters (SS), 8 typical sweaters, and 6 patients with CF
Exercise Intervention:Dehydration exercise: Cycling in heated environment at 50% of VO2 max; 20-minute bouts with 5-minute rest breaks.
Cycling continued until subjectt lost 3% of body weight via sweating.
Outcome Measures and Results:

1. Rate of perceive Thirst

Thirst stimulus was not affected by high Na+ concentration in sweat; likely triggered by decreased serum osmolality and decreased
plasma volume (hypovolemia)
2. Volume of fluid ingested after exercise
CF patients drank 40% less fluid after exercise than controls
3. Na and Cl- concentrations in sweat
+

Increased concentrations of Na+ and Cl- in the sweat in both SS and CF patients as compared to controls
4. Serum Osmolality, Free Water (FW), Plasma volume (PV)
SS and CF patients had decreased osmolality rise and more plasma volume (PV) loss with increased dehydration; The concentration
of Na+ in the sweat was directly proportional to the plasma volume percent loss.

Two studies by Brown et al. addressed the impact exercise has on the sweat glands in patients with cystic fibrosis.[78],[77] In Study 1 by Brown et
al., the authors concluded that the abundance of ENaC channels on the apical membrane in the sweat glands did not differ between groups, while
CFTR was less present in the membranes of patients with CF.[78] Because both ENaC and CFTR are activated together in the sweat glands,
ENaC is not regulated with malfunctioning CFTR, resulting in a higher NaCl concentration in sweat after exercise.[78] Additionally, the hormones
aldosterone (ALDO) and vasopressin (AVP) have been shown to regulate Na+ and fluid, and, therefore, may have a potential effect on the sweat
glands during exercise however the effect in CF is unknown[78] The authors found that in the SS group, there were higher levels of AVP as
compared to the controls and subjects with CF.[78] They attributed this to potentially be a compensatory measure to regulate fluid levels in
response to an increased Na+ sweat concentration.[78] There was no difference in the levels of ALDO amongst all groups after exercise.[78]

Study 2 by Brown et al. stressed the importance of hydration in individuals with CF. It is important to understand that during exercise, patients with
CF must be careful as they are at risk for becoming dehydrated.[9],[77] The high concentration of NaCl in the sweat of individuals with CF
decreases the serum osmolality due to less Na+ (solute) in the blood.[77] This causes the person to have decreased thirst, and subsequently, they
do not consume enough water, leading to dehydration.[9],[79],[33] However, Brown et al. hypothesized that there is still is a thirst stimulus present
by way of another mechanism.[77] The authors concluded that despite the increased concentrations of NaCl in the sweat and a decreased serum
osmolality following exercise, a decreased plasma volume provided a thirst stimulus for patients with CF.[77] Though patients with CF consumed
40% less fluid than the control or SS group after exercise, this was likely attributed to the severe decrease in serum osmolality and the type of fluid
provided at the end of the exercise which was hypotonic (low in solute concentration).[77] Had a more hypertonic (increased solutes) liquid been
provided after exercise, the patients with CF may have consumed more because increasing the solute intake would increase the serum osmolality,
creating a thirst stimulus. Had their serum osmolality been higher following exercise, the consumption of a hypotonic beverage may have been
greater as the body wants to meet the increased number of solutes in the blood with a low osmotic solution such as water.[77] Without the increase
in solutes in the blood after exercise, the stimulus to drink a hypotonic fluid is blunted.[77] Drinking fluids with a low osmolality such as water
causes the blood serum osmolality to fall and decreases the thirst stimulus before a patient has drank enough liquid to replace loss of the solutes
in the blood.[77]

Recommendations
Although the effects of exercise on the sweat glands are still being studied in patients with CF during exercise, it is imperative that these individuals
maintain proper hydration to prevent dehydration despite having a thirst stimulus. Therefore, it is recommended that patients with CF drink a
hypertonic solution (more salt) following exercise to replace the loss of solutes (salt) in the blood and continue to drink even after they no longer
have a thirst stimulus. Additionally, in Study 1 by Brown et al., in non-CF patients who were salty sweaters, the baseline AVP was higher than the
healthy controls, while there was no difference in subjects with CF.[77] Consequently, it is difficult to make exercise recommendations at this time
without more research. However, it has been speculated that if an increase in sweat Na+ concentration increases AVP, AVP will increase plasma
volume, which is important for diluting sweat and retaining serum electrolytes.[9][77]

IV. Exercise and Inflammatory Cytokines

The effects of exercise on inflammatory cytokines in healthy individuals have been well documented.[81] There is well over 1800 studies that have
investigated the immune response to exercise.[82] Briefly, pro-and anti-inflammatory cytokines such as IL-6, TNF-, and IL-10 increase in
response to a bout of exercise.[81] Due to the fact that muscle activation releases IL-6,[81],[83],[84] it is unsurprising that exercise results in
increased levels of this cytokine. The levels of IL-6 can rise significantly in an acute bout of exercise in a healthy individual.[81],[85] The degree to
which these cytokines are increased, decreased, sustained, or suppressed is mediated by the duration, intensity, and type of exercise in healthy
individuals.[81] Strenuous and eccentric exercise are two types of exercise that have been demonstrated to affect cytokines the greatest.[81],[86],[
87],[88],[89],[90] Furthermore, it has been found that people who participate in extreme exercise (such as marathons) are at greater risk for
infection due to a compromised immune system as a result of a depressed cytokine response from this high level of exercise.[81],[91] Conversely,
the effects of acute bouts of exercise on inflammatory cytokines were found to be transient in nature regardless of the intensity level of exercise.[81
] Interestingly, it has also been demonstrated that healthy individuals who chronically exercise have a lower resting level of inflammatory cytokines
than those who do not regularly exercise.[81],[92] This finding implies that exercise may have a potential benefit on people with inflammatory
diseases.[81],[85],[93] However, due to the nature of acute bouts of exercise increasing inflammatory cytokines, people with inflammatory diseases
must proceed with caution and exercise at safe intensities and dosages so as not to exacerbate their disease.[81] Nonetheless, evidence is
emerging to suggest that chronic exercise may attenuate the inflammatory response of a single acute bout of exercise.[81],[90],[94]

Exercise is generally believed to be an important component of rehabilitation for many chronic conditions.[81],[95] However, therapists must be
aware of the potential harmful effects of exercise on conditions with inflammatory processes. It is known that people with CF have higher resting
levels of inflammatory cytokines than in healthy individuals.[96],[97],[98],[99] It is not advantageous to increase levels of IL-6 or TNF- in people
with CF due to potential increases in muscle wasting and bone catabolism.[96],[97],[100],[101],[102],[103],[104],[105] Therefore, it is of interest to
discover the effects of exercise on inflammatory cytokines in order to determine if exercise is safe in people with CF. If exercise is safe, it is
important to determine the appropriate intensity and dosage at which exercise will yield the greatest benefit.

A. IL-6 & TNF-

The evidence on the effects of exercise on IL-6 and TNF- specifically in CF is emerging. Despite the fact that the response of these inflammatory
cytokines to exercise has been well researched, the literature in CF is still in its infancy. To date, only four studies have looked at the relationship
between exercise and inflammatory cytokines in CF.[96],[97],[104],[106] Additionally, experiments in animal models have not yet been studied. In a
systematic review from 2009, the effects of exercise on inflammation in various inflammatory diseases (including CF) in children and adults were
investigated.[81] Ploeger et al. concluded that, in children and adults, acute bouts of exercise will generally raise inflammatory cytokines in
conditions such as CF.[81] Since this reviews publication, more research has been conducted to further elucidate the effects of exercise in people
with CF. Refer to table 1 for the current evidence on the effects of exercise on inflammatory cytokines in CF.

The first study that was published on this topic was in 2001 by Tirakitsoontorn et al.[104] The major findings of this study, in terms inflammatory
cytokines, were that an intense bout of acute exercise significantly increased IL-6 and TNF- in children with CF compared to healthy controls and
that children with CF on anti-inflammatory drugs (ibuprofen) had a smaller increase in these cytokines.[104] Interestingly, IL-6 levels peaked during
the 90-minute post-exercise bout whereas TNF- peaked immediately following exercise.[104] Additionally, this study also looked at the
relationship of these cytokines to growth factors after exercise, which is described below. From the methodology of this study, it is difficult to
determine if an intense bout of exercise was truly measured. The exercise protocol consisted of ten bouts of cycling for two minutes at 50%
VO2peak with one minute rest breaks between bouts.[104] It could be argued that this protocol measured intermittent moderate-intensity bouts of
exercise. A VO2peak of 50% would suggest moderate level effort, and thus, this study does not investigate intense level exercise. While these
results provide important information about inflammatory factors in CF during exercise, this study has several limitations. Thus, the results of this
study must be interpreted with caution. First, this was not a randomized controlled trial, but rather a two-group, non-random pre-test post-test
design. Second, these results are based upon a very small sample size. It is also unknown if the children with CF were stable or in an exacerbation
period. Furthermore, it is unknown as to whether or not the children were chronic exercisers or sedentary prior to this study. Finally, this study does
not investigate the effects of an exercise program but rather just one episode of exercise and does not complete adequate follow-up. Therefore,
from this study it is unknown what effects training may have on these cytokines or long-term effects of increased cytokine levels. This is important
to understand when considering that people with CF already have a heightened baseline of inflammatory cytokines.[96],[97],[98],[99]

The second study published in 2006 by Ionescu et al. also looked at IL-6 and TNF- in response to a bout of moderate-intensity exercise in adults
(box stepping until exhaustion for a maximum of 20 minutes).[97] Growth factors were also investigated as described below. This study had similar
findings to Tirakitsoontorn et al.[104] They found that in comparison to healthy controls, IL-6 and TNF- levels were significantly greater post-
exercise.[97] Additionally, similar to the study above, it was observed that IL-6 and TNF- peaked immediately after exercise, but IL-6
concentrations remained elevated at 30 minutes and 120 minutes post-exercise.[97] The elevation of IL-6 for 2 hours was not observed in the
healthy controls.[97] Though these findings support what was found by Tirakitsoontorn et al. in an adult population, this study also has several
limitations. Namely, this study was limited by lack of randomization, small sample size, and lack of generalizability beyond one bout of exercise.

A third study was conducted by Moeller et al. in 2010.[106] This study took place in Switzerland where the cool temperatures are believed to be
optimal for exercise in people with pulmonary conditions to prevent heat exhaustion.[106] Several cytokines were investigated in this study, which
are found in table 1, including IL-6 and TNF- during a three week inpatient rehabilitation program for children with a diversified exercise program.[
106] However, no significant changes were noted in sputum cytokines. This study has numerous weaknesses. First, cytokines were analyzed from
sputum production from each child as opposed to from blood or urine analysis.[106] Because of this, sputum could only be collected if the child
produced it when they coughed and was only collected in the morning after chest physical therapy.[106] Therefore, cytokine levels were not
assessed around physical activity. In this way, the cytokine measurements were not an accurate portrayal of exercise response. Furthermore, this
study poorly describes the exercise interventions as duration, intensity, and exact types exercises are unknown. Finally, there was no
randomization, no control group, and a small sample size.

Finally, Nguyen et al. compared the differences between continuous moderate-intensity exercise and intermittent high-intensity exercise on
inflammatory cytokines and growth factors in children with CF.[96] As found in previous studies,[97],[98],[99],[107], the children had a significantly
higher baseline concentration of IL-6 and TNF-.[96] During the middle of exercise for both exercise conditions, no significant differences were
noted. However, immediately after exercise, IL-6 was significantly higher in both the CF and healthy age-matched control groups that participated
in continuous moderate-intensity cycling. Importantly, IL-6 levels were not significantly elevated in the CF group that participated in intermittent,
high-intensity cycling. [96] For all groups, TNF- was not significantly increased immediately after exercise.[96] In fact, TNF- was not significantly
different at any point during exercise or post-exercise.[96] This finding was surprising, as it contradicts the previous studies above which found that
peak TNF- levels in response to moderate level exercise were significantly increased immediately after exercise.[97],[104] At 30 minutes and 60
minutes post-exercise, IL-6 was significantly higher in both the CF and healthy age-matched control groups that participated in continuous
moderate-intensity cycling but again were not elevated in the CF group that participated in intermittent, high-intensity cycling.[96] A strength of this
study was that the control group was age-matched to the CF groups in each condition, which helps control for potential age differences especially
in such a small sample. However, this study was not clear on if there was random assignment to each exercise condition or if all participants
completed each condition in a cross-over design. Furthermore, this study is limited by a small sample size and potential lack of randomization.

B. Precursors to IL-6 and TNF-

Briefly, two studies looked at monocytes in response to exercise in CF. Monocytes are precursors to macrophages, which produce IL-6 and TNF-.
[96],[108] Refer to table 2 for study descriptions and findings. Both studies were conducted by Boas et al.[107],[109] and investigated several
immune mediators in response to exercise. For the purposes of this discussion, however, only the effects on monocytes will be reported. In
summary, both studies revealed that an intense bout of exercise resulted in significant increases in total monocyte count in children with CF and in
healthy controls immediately post-exercise, which effects were attenuated after 1 hour.[107],[109] Children with CF had higher baseline monocytes
and a greater increase in monocytes post-exercise.[107],[109] The authors concluded that children with CF immune function responds in a similar
manner to exercise as in healthy children.[107],[109] These studies were also limited by non-randomization and small sample size.

Table 1: Effects of Exercise on Inflammatory Cytokines

Level of Age Outcome

Study Question Subjects Intervention Findings
Evidence Range Measures
Significant increase in IL-6 in
Both groups
both groups (p<0.002). IL-6
Effect of *14 children performed 2
*CF increased greatest in children
brief bout of (8 female) minute bouts of
group:7- Serum with CF not on ibuprofen and
intense with CF (9 exercise on
2 group 17 and Urine smallest in healthy controls.TNF-
Tirakitsoontorn exercise on taking cycle
nonrandom years cytokines: significantly increased
et al., 2001[ catabolic ibuprofen, 5 ergometer, at
pretest- *Healthy IL-6, TNF- immediately after exercise with
104] and anabolic no NSAIDs) 50% of peak
posttest group: , IL-1, the greatest increase in children
mediators in *14 healthy VO2, 10 times,
8-15 IL-1ra with CF not on ibuprofen and the
children with children (7 with 1 minute
years smallest in healthy controls. No
CF female) rest between
effect was observed for IL-1,
bouts
IL-1ra.
*11 adults Both pre-exercise and post-
with CF (6 *CF exercise serum concentrations
female) after group: of IL-6 (p<0.01) and TNF-
14 day mean (p<0.05) were significantly
Effect of inpatient age Box-stepped greater in the CF group
moderate- 2 group treatment of 28.2 (20 cm), 15 Serum compared to the healthy
Ionescu et al., intensity nonrandom acute years steps/min until cytokines: controls. Peak IL-6 and TNF-
2006[97] exercise on pretest- exacerbation *Healthy exhaustion for a IL-6, TNF- levels were observed at the end
inflammatory posttest *12 healthy group: maximum of 20 of exercise. IL-6 remained
mediators adults (7 mean minutes significantly elevated for 30 min
female) not age (p<0.01) and 2 hours (p=0.016)
on a regular 29.9 post-exercise in the CF group,
exercise years while IL-6 only remained
program elevated in healthy subjects for
30 min.
3-week
inpatient
rehabilitation
program which
consisted of
chest PT
2x/day,
gymnastic
program in the
Effect of a 3
morning (warm-
week
up,
intensive Cytokines
cardiovascular
rehabilitation Median in sputum:
One group, 18 children endurance
Moeller et al., program on age IL-1b, IL- No significant change in sputum
pretest- with stable training
2010[106] airway 12.1 6, IL-8, IL- cytokines after 3 week program
posttest CF exercises in
inflammation years 10, IL-12,
conjunction with
in children TNF-
coordinative
with stable
exercises and
CF
stretching, and
a diversified
 physical activity
program 1-
2x/day (cycling,
walking, hiking,
climbing,
swimming, and
rollerblading
*Pre-exercise: Children with CF
Moderate- had significantly higher levels of
intensity cytokines *Mid-point of exercise:
continuous No significant differences
exercise (MICE) *Immediately after exercise: IL-6
group: 2 x 30 levels were significantly higher in
min bout of CF MICE group and also in the
cycling at 50% age-matched MICE control
Effect of
peak compared to pre-exercise
moderate-
mechanical (p<0.05), but were not
intensity, *CF
power with 6 significantly elevated in the HIIE.
continuous group:
*12 children minute rest No significant difference for
exercise 11.3-
with CF (2 break between TNF-. *30 min post: IL-6 levels
versus a 2 group 17.5 Plasma
female) *12 bouts High- were significantly higher in CF
Nguyen et al. high- nonrandom years cytokines:
healthy intensity MICE group and also in the age-
2011[96] intensity, pretest- *Healthy IL-6, TNF-
children intermittent matched MICE control
intermittent posttest group:
(age- exercise (HIIE) compared to pre-exercise
exercise on 10.5-
matched) group: 6 series (p<0.001), but were not
inflammatory 17.5
of 4x15 sec significantly elevated in the HIIE.
responses in years
bouts of cycling No significant difference for
children with
at 100% peak TNF-. *60 min post: IL-6 levels
CF
mechanical were significantly higher in CF
power with 1 MICE group and also in the age-
minute rest matched MICE control
between bouts compared to pre-exercise
and a 6 minute (p<0.01), but were not
rest between significantly elevated in the HIIE.
each series. No significant difference for
TNF-.

Table 2: Effects of Exercise on Precursors to Inflammatory Cytokines

Level of Age Outcome

Study Question Subjects Intervention Findings
Evidence Range Measures
Graded maximal
What are
*CF exercise test on cycle
potential *12
group: ergometer to exhaustion
Boas, mediators of children Both the CF and healthy
2 group 8-17 at rate of 60
Danduran, immune with Serum control group had a
nonrandom years revolutions/min and
McBride response stable Leukocytes: significant increase in
pretest- *Healthy 90% max heart rate.
et al., during CF *12 Monocytes monocyte count in response
posttest group: Increase in power was
2000[109] exercise in healthy to exercise.
8-17 incrementally (10, 15, or
children with children
years 20 watts) made based
CF?
on subject height
Serum monocytes were
*15 significantly greater for the
Graded maximal
Does immune children CF group than the healthy
*CF exercise test on cycle
function in with control group at baseline.
group: ergometer to exhaustion
Boas, children with stable Both the CF and healthy
2 group 8-21 at rate of 60
Danduran, CF respond CF (8 Serum control group had a
nonrandom years revolutions/min and
McColley to exercise female) Leukocytes: significant increase in
pretest- *Healthy 90% max heart rate.
et al., similarly to *15 Monocytes monocyte count 3 minutes
posttest group: Increase in power was
2000[107] the response healthy post exercise, but no
8-18 incrementally (10, 15, or
in healthy children significant difference 1 hour
years 20 watts) made based
children? (6 after exercise. The CF group
on subject height
female) had a larger increase in
monocytes than the control.

C. IL-10
Two studies have measured the effect of exercise on the anti-inflammatory cytokine IL-10 in people with CF.[106],[110] In their study, Moeller et al.[
106] measured sputum IL-10 levels in addition to the pro-inflammatory cytokine levels described above. Consistent with the results of the pro-
inflammatory cytokine measurement, they found no change in sputum IL-10 following the three-week rehabilitation program.[106] Another study by
Sahlberg et al.[110] measured serum levels of pro-inflammatory and anti-inflammatory cytokines before and after a six-month exercise program in
people with CF. The program consisted of three, weekly 30-45 minute exercise sessions with one group completing endurance training and the
other group completing resistance training for three months.[110] The final three months of the program consisted of a mixed training program for
both groups that followed the same training schedule.[110] The authors found no change in serum IL-10 levels in either the endurance training
group or the resistance training group following the exercise intervention.[110] The limitations of this study included a small sample size, lack of
randomization, lack of a control group, and differences in cytokine measurements between the groups at baseline.[110] Clearly, both studies have
considerable limitations and provide unreliable information about the effect of exercise on IL-10 in people with CF. The lack of a control group in
both studies prevents comparison between the effects of exercise versus no exercise on IL-10 level in people with CF. Therefore, more research is
needed to determine how exercise truly affects IL-10 in people with CF.

Implications
Exercise is believed to be important for bone and muscle growth and development, which is diminished in CF.[96],[97],[112] It is therefore important
to understand the inflammatory response to exercise in CF to attempt to diminish this effect. In general, the studies above show that IL-6, TNF-,
and monocytes significantly increase in response to exercise.[96],[97],[104] Though, this effect may be attenuated in children with CF on anti-
inflammatory drugs.[104] There does not appear to be age or sex-related differences to inflammatory responses from exercise in people with CF
based on the current evidence. Additionally, it appears that IL-6 remains elevated for a longer period of time than TNF-.[97],[104] It is therefore
important to target exercise intensities and durations that will prevent IL-6 from increasing in order to prevent the most damaging effects associated
with this cytokine. Nguyen et al. found that high-intensity intermittent exercise does not result in a significant increase in IL-6 or TNF.[96]

From these studies some contradictions did arise. First, Moeller et al. found no significant changes in inflammatory cytokines during a 3-week
exercise program.[106] This was probably due to the fact that cytokines were not assessed directly after or around a bout of exercise. Furthermore,
this was a poorly designed study and the validity of its results are uncertain. Second, Nguyen et al. did not find a significant increase in TNF- to
any exercise intensity or duration like previous reports have.[96] The reason for this is currently unknown and more research is needed to better
understand the mechanisms involved.

The research on the effects of exercise on IL-10 in people with CF is weak but indicates that IL-10 does not change in response to exercise in this
population.[106],[110] More research is needed because levels of IL-10 appear to be positively correlated with amount of weekly exercise in people
without CF.[111] If exercise is actually able to increase or prevent decrease in IL-10 in people with CF, it could help to prevent the negative effects
of inflammation in this population.
All these results are based on weak evidence with very few studies and therefore the findings cannot be generalized. In addition, the studies are
difficult to compare as exercise protocols, methods of measurement, clinical status of participants, and cellular factors of interest varied. Future
randomized controlled trials are needed to confirm these findings, specifically in animal models, to elucidate the cellular mechanisms. More
controlled research with larger samples are also needed in humans to confirm these findings. Future studies will also need to investigate functional
and quality of life related outcomes measures in addition to these cellular mechanisms to determine clinical relevance of these findings.
Furthermore, in addition to looking at inflammatory factors during and after exercise, future studies need to investigate the cellular effects in the
bone and muscle after exercise to confirm that catabolic changes are occuring as a result of increased inflammatory cytokines. In some instances,
IL-6 is thought to act as an anti-inflmmatory cytokine rather than pro-inflammatory with muscle contraction.[96],[113] However, there is currently no
evidence to support this notion in CF. This is an important question regarding exercise prescription. Additionally, no studies have adequately looked
at the effects of chronic exercise in people with CF with respect to inflammatory mediators and catabolic versus anabolic effects on muscle and
bone. This is a crucial question for this disease and should be a direction for future research.

Recommendations
Based on the current evidence, it appears that in order to avoid an inflammatory response, high-intensity intermittent exercise (6 series of 4x15
second bouts of 100% mechanical power with 1-minute rest between bouts and 6-minute rest between series) is best for people with CF.[96]

V. Exercise and Growth Factors

Growth Hormone (GH) and insulin-like growth factor 1 (IGF-1) are important for mediating the growth of bone and muscle in people with CF,
thereby, preventing or diminishing muscle wasting and maintaining bone mineral density.[96],[97] It is known that TNF- has the ability to reduce
concentrations of growth hormone and that TNF- and IL-6 are associated with protein catabolism.[96],[97],[112] The studies described above
detailed how exercise can result in increases in inflammatory cytokines. While this is not advantageous, the studies described below detail how
exercise can increase levels of growth factors, which have beneficial effects. The challenge is to find the balance between eliciting the negative
effects of cytokines and the positive effects of growth factors with exercise prescription.

A. Growth Hormone & IGF-1

The studies by Tirakitsoontorn et al., Ionescu et al., and Nguyen et al. (which are described in detail above and in table 1 and table 3) investigated
the effects of exercise on growth factors in children and adults with CF. In summary, exercise of any intensity had no effect on IGF-1 in people with
CF.[96],[97],[104] However, growth hormone was found to significantly increase in response to exercise of both moderate and high intensities and
to exercise that was continuous and intermittent in duration.[96],[104] Furthermore, it was found that growth hormone increased the most in
response to continuous acute bouts of moderate-intensity exercise.[96] These results are, as with the findings above, based on a low level of
evidence.

Table 3: Effects of Exercise on Growth Factors

Level of Age Outcome

Study Question Subjects Intervention Findings
Evidence Range Measures
Both groups
Effect of *14 children GH increased significantly in
*CF performed 2
brief bout of (8 female) both groups (p<0.001), no
group:7- minute bouts of
intense with CF (9 significant difference between
2 group 17 exercise on Serum
Tirakitsoontorn exercise on taking groups. Significant decrease in
nonrandom years cycle ergometer, Growth
et al., 2001[ catabolic ibuprofen, 5 IGF-1 in both groups which was
pretest- *Healthy at 50% of peak Factors:
104] and anabolic no NSAIDs) observed at 60 minutes post
posttest group: VO2, 10 times, GH, IGF-1
mediators in *14 healthy exercise (p<0.001), no
8-15 with 1 minute
children with children (7 significant difference between
years rest between
CF female) groups
bouts
*11 adults
with CF (6 *CF
female) after group:
14 day mean
Effect of inpatient age Box-stepped
moderate- 2 group treatment of 28.2 (20 cm), 15 Serum
Ionescu et al., intensity nonrandom acute years steps/min until growth
No significant difference
2006[97] exercise on pretest- exacerbation *Healthy exhaustion for a factors:
inflammatory posttest *12 healthy group: maximum of 20 IGF-1
mediators adults (7 mean minutes
female) not age
on a regular 29.9
exercise years
program
Pre-exercise: No significant
Moderate- differences between groups
intensity Mid-point of exercise:
continuous Significant increases (p<0.001)
exercise (MICE) in GH for both MICE and HIIE
group: 2 x 30 groups compared to pre-
min bout of exercise for both CF and age-
Effect of matched controls. The largest
cycling at 50%
moderate- increase in GH was observed in
peak mechanical
intensity, the MICE groups. No significant
*CF power with 6
continuous differences for IGF-1.
group: minute rest
exercise *12 children Immediately after exercise: For
11.3- break between
versus a with CF (2 the CF group, there was a
2 group 17.5 bouts High- Plasma
high- female) *12 significant increase (p<0.01) in
Nguyen et al. nonrandom years intensity Growth
intensity, healthy GH for MICE only; no
2011[96] pretest- *Healthy intermittent Factors:
intermittent children significant difference for HIIE
posttest group: exercise (HIIE) GH, IGF-1
exercise on (age- compared to pre-exercise. In
10.5- group: 6 series
growth matched) the age-matched controls, there
17.5 of 4x15 sec
factor was a significant difference in
years bouts of cycling
response in GH for both MICE (P<0.001)
at 100% peak
children with and HIIE (P<0.01) compared to
mechanical
CF pre-exercise. The largest
power with 1
minute rest increase in GH was observed in
between bouts the MICE groups. No significant
and a 6 minute differences for IGF-1. 30 min
rest between post: No significant differences
each series. 60 min post: No significant
differences

Implications
Although these results suggest that moderate-level, continuous exercise is optimal for production of growth hormone, IL-6 (which can stay
circulating in the blood 2 hours post-exercise[97]) significantly increases at this level of intensity[96] and TNF- may increase as well.[104] Due to
the fact that growth hormone was found to increase with high-intensity intermittent exercise without an increase in inflammatory cytokines,[96] this
prescription of exercise is more optimal for people with CF. However, the level of intensity may not matter in this instance. It may be that it is the
intermittent nature of the exercise protocol that is important in mediating inflammatory factors, but there is currently no research to speak to this
hypothesis. Future studies should compare the effects of moderate-intensity continuous, moderate-intensity intermittent, high-intensity continuous,
and high-intensity intermittent exercise on growth factors and inflammatory cytokines in people with CF. Additionally, future studies need to
investigate the effects at the level of the bone and muscle in conjunction with growth and inflammatory factors to determine at what level exercise
creates greater anabolic than catabolic effects. Again, these results are based on a few, low level of evidence studies and, therefore, should be
interpreted with caution. More controlled research and research in animal models is needed to confirm these results.

Recommendations
Based on the current evidence, in order to optimize the production of growth hormone without increasing inflammatory cytokines, it appears that
high-intensity intermittent exercise (6 series of 4x15 second bouts of 100% mechanical power with 1-minute rest between bouts and 6-minute rest
between series) is best for people with CF.[96]

VI. Exercise and Bone Mineral Density

With an increasing lifespan and 38% of young adults with CF having osteopenia and 23.5% having osteoporosis,[114] strategies to maintain bone
mineral density (BMD) are essential in this population.[115] These include proper nutrition and supplementation to promote bone health, minimal
use of glucocorticoids, aggressive treatment of pulmonary infections, and performance of exercise.[115] For the purpose of this page, only exercise
will be discussed. The causes and implications of low BMD in CF are described in the musculoskeletal and inflammatory sections of the cell
biology page. Two key concepts that contribute to BMD in CF include the relationship between the inflammatory factors (IL-6 and TNF-) and
growth hormone. As mentioned previously, IL-6 and TNF- have been associated with low BMD[97],[103],[104] due to these cytokines influence
on increasing osteoclast activity.[116], while growth hormone functions to improve bone growth.[96] Because of these influences, the above
recommendation in regards to exercise and growth hormone is important in BMD maintenance. Based on the aforementioned current but weak
evidence, high-intensity intermittent exercise is optimal for promoting growth hormone without increasing inflammatory cytokines[96] and should be
the most advantageous for bone health.

Although there is some evidence in regards to the effect of exercise on levels of IL-6, TNF-, and growth hormone, these studies did not consider
the effect on BMD. Furthermore, while there have been several cross-sectional and retrospective studies that have found a positive correlation
between level of physical activity and CF,[117],[118][119] there have been no intervention studies to analyze the effects of specific exercise on
BMD in individuals with CF. Animal and human studies need to focus on determining the connection between exercise and the effects on cell
factors (IL-6, TNF-, and growth hormone) and BMD in subjects with CF. Randomized controlled trials need to be conducted in humans with CF to
determine the most appropriate frequency, intensity, and duration of exercise for optimal bone health.

VII. Exercise and Oxidative Stress

As described in Cystic Fibrosis Cell Bio, the epithelial cells of people with CF have higher levels of reactive oxygen species (ROS) than those of
people without CF, indicating the presence of oxidative stress within the cells.[120],[121],[122] The effect of exercise on oxidative stress in the cells
of people with CF is unknown because no research has been completed in this area. Therefore, in order to form a hypothesis about the effects of
exercise on oxidative stress in people with CF, it is necessary to look at the effects of exercise on people without CF.

In the general population, acute exercise increases oxidative stress by increasing the production of ROS in the electron transport chain, which then
leak from the mitochondria.[123],[124] Activity of xanthine oxidase and NAD(P)H oxidase enzymes during exercise also increase ROS.[123],[124]
Studies indicate that although ROS levels increase in response to acute exercise, there is an adaptation response to long-term, regular exercise.[
123],[125],[126] A study by Falone et al.[125] compared oxidative stress in trained versus sedentary males. They found that the trained subjects
had a higher antioxidant capacity and a reduced acute oxidative response to individual bouts of exercise compared to the sedentary subjects.[125]
Based on these results, the authors concluded that moderate-intensity aerobic exercise can increase antioxidant defenses.[125]

The mechanism by which this adaptation response is believed to occur is through activation of the nuclear factor kappa B (NF-B) transcription
factor by the increased ROS within the cell following exercise.[126],[127],[128],[129] Once activated, NF-B increases the transcription of
antioxidant enzymes, including mitochondrial Mn-superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS).[126],[127],[128],[129]
A study by Hollander et al.[127] found that an exhaustive bout of exercise led to increased binding of NF-B in rat skeletal muscle and that the NF-
B binding remained increased for at least 48 hours following exercise. This study also found that an exhaustive exercise bout led to increased
MnSOD mRNA but no increase in MnSOD protein levels in the rat deep vastus lateralis muscle for at least 48 hours following the exercise.[127]
The authors stated that chronic exercise may be required in order to increase the level of MnSOD protein.[127] However, in the rat superficial
vastus lateralis muscle, increased MnSOD protein levels were found following the exhaustive exercise bout.[127] This study demonstrated that
exercise increases NF-B binding, which then leads to increased antioxidant enzyme gene expression.[127] Radak et al.[130] explained that this
adaptive mechanism improves the cell response to oxidative stress over time, and that the effect is likely systemic.

These results have potential implications for exercise in people with CF. While the initial increase in ROS that occurs with acute exercise would be
unfavorable for this population due to the already elevated ROS levels, an improved long-term antioxidant effect with regular exercise would be
beneficial. Although the antioxidant effect of long-term exercise may be different in people with CF due to differences within the cell, it may be
possible that some of the mechanisms are similar. People with CF have decreased levels of the antioxidant glucothione (GSH) due to CFTR
dyfunction, which is likely the cause of oxidative stress within the cell.[120] If the antioxidant enzymes MnSOD and iNOS are able to function
despite CFTR dysfunction, they may provide a way to compensate for decreased GSH. Increasing the levels of these enzymes through long-term
exercise in people with CF could potentially decrease the level of ROS. Therefore, regular moderate-intensity exercise could lead to decreased
oxidative stress within the epithelial cells of people with CF. However, it should be noted that this idea is purely theoretical and has not been
studied in research.

Another theory regarding the effect of exercise on oxidative stress in the cells of people with CF was proposed by Cholewa et al.[10] This theory
suggests that the activation of AMPK by exercise may lead to decreased oxidative stress within the airway epithelial cells of people with CF.[10]
This theory demonstrates potential because AMPK activation has been found to decrease ROS levels within the epithelial cells of other organs in
people without CF.[10][72],[73],[74],[131] One mechanism by which AMPK may reduce ROS levels is through inhibition of protein kinase C, which
then reduces NAD(P)H oxidase activity.[131] The reduced NAD(P)H oxidase activity then results in decreased production of ROS.[131] However,
this response was found following glucose-induced oxidative stress in human umbilical endothelial cells[131] and appears to differ from other
studies showing AMPK activation of protein kinase C.[69] Future research will need to test the effects of exercise-induced AMPK activation in the
airway epithelial cells of people with CF to determine if the same effect occurs in the airway in this population. If indeed exercise-induced AMPK
activation is found to reduce ROS levels in the airway epithelial cells of people with CF, this cellular mechanism could provide evidence to support
exercise interventions for this population in the future.

Implications
While there is no research on the effects of exercise on oxidative stress in people with CF, theoretically, regular exercise may decrease oxidative
stress in this population. However, exercise also has the potential to increase oxidative stress. Therefore, no reliable exercise recommendations
can be made based on the effect of exercise on oxidative stress, but the clinician should be aware that exercise may impact oxidative stress in
people with CF and look for future research on this topic.

VIII. Sex related differences and Exercise

Sex related differences between males and females in CF have only been recently studied and prior to, there was only speculation that there were
gender differences between males and females with CF. While CF is not sex linked, studies have shown that women may have faster lung function
decline, contract pneuomonia earlier on than males,[132] have more exacerbations and flare ups,[133] and have a decreased lifespan and have
increased lung disease[134],[135]. In a study by Zeitlin et al, it was reported that in women, elevated levels of 17 estradiol can reduce Ca2+-
activated chloride channels (CaCC).[136] As discovered previously, CaCCs are important as they provide a means for Cl- secretion when CFTR is
defective.[137] Therefore, a reduction in function of the CaCC can decrease mucus clearance, dehydrate the lungs, and cause an increased risk
for infection.[136] The study by Coakley hypothesized that 17 estradiol (receptor mediated) can actually inhibit Ca2+ activation, which is important
for homeostasis and maintaining adequate ASL in the airways in patients with CF.[138]

In females, the main form of estrogen present is 17 estradiol and it achieves its highest levels a few days prior to ovulation.[138] Interestingly,
both Ca2+ and IP3 signaling pathways influence 17 estradiol action.[139],[140],[141] To determine what effect estrogen levels had on Ca2+
signaling, nasal TPD was calculated based on the same methods as previously discussed.[11] Readings were taken throughout a womans
monthly reproductive cycle and the authors concluded that when estrogen was increased 4 times the normal level (in days prior to ovulation), UTP-
stimulated Cl- secretion was inhibited by 50%.[138] When looking at polarized airway cultures, they concluded that 17 estradiol receptor inhibited
the influx of Ca2+ which would decrease Cl- secretion and decrease ASL volume as shown in the figure below.[138] They found that there was no
difference in the amiloride-sensitive TPD magnitude of change regardless of estrogen level in both patients with CF and patients without CF,
indicating that estrogen levels did not have a direct effect on Na+ absorption.[138] UTP-stimulation via addition of a low Cl- solution showed a
decrease in TPD of about 50% in patients with CF and 40% in patients without CF during times of maximal estrogen presence.[138] The authors
also concluded that the effects of increased estrogen (17 estradiol) were only seen in the P2 signaling pathway and that the c-AMP and the CFTR
pathways were not affected.[138] In fact, it was concluded in a variety of studies that an increase in 17 estradiol actually increased CFTR
expression.[142],[143] While there is conflicting evidence, this may be important to understanding the upregulation of CFTR. Conversely, at higher
levels of 17 estradiol in the study by Coakley et al., there was no increase in Cl- secretion with isoprotenerol to facilitate Cl- secretion through c-
AMP mediated pathways that utilize CFTR.[138] The authors explained that while in some studies it was determined that 17 estradiol could
upregulate CFTR, it may not be enough to effect the TPD or counteract the inhibitory effect 17 estradiol had on Ca2+-mediated pathways.[136]
Coakley also found that anti-estrogen therapy such as Tamoxifen may increase Cl- secreted by limiting the inhibitory effects of Ca2+ pathways from
increased estrogen.[138] However, it is important to consider the side effects of tamoxifen such as possible stroke, deep vein thrombosis (DVT),
cancer of the uterus, cataracts, or pulmonary embolisms to name a few.[136]

Figure 3: Estrogen and its Effect on ASL Volume[136]

http://www.jci.org/articles/view/37778/figure/1

Implications

While the effect of exercise is unknown on the modulation of 17 estradiol and the effects it has on Cl- secretion, it is possible that exercise can
increase Ca2+ signaling and thus increase Cl- secretion with the CaCC via an increase in ATP. As stated previously, exercise is accompanied with
an increased ventilation rate which can cause phasic stress in the airways.[27] The phasic stress can trigger the realease of ATP which can
stimulate P2Y2 to increase Cl- secretions.[27] However, it is important to consider another concept concluded by Coakley et al. as they found that
after 48 hours of phasic stress in in vitro HBEC (Human bronchial epithelial cells), when estrogen levels increase even for an hour, there was a
50% reduction in ASL volume.[138] These values were taken in vitro so continuous ATP activation during exercise may still have a different effect.
Additionally, while Tamoxifen was effective in increasing and maintaining Cl- secretions in the presence of increased estrogen levels, the side
effects of tamofixen may outweigh its benefits.[136] If the negative effects of estrogen can be reduced even in the presence of increased estrogen,
this may be very beneficial for women.

Recommendations
In conclusion, while there is no direct evidence to prove that exercise can actually decrease the inhibitory effects increased estrogen levels have
on Cl- secretion, it is theorized that by way of ATP activation and subsequent activation of CaCC, exercise may potentially be able to increase or
maintain adequate ASL volume during periods of high estrogen levels and decrease a females suseceptibility to infection during this time.

IX. Conclusion and Recommendations for Exercise in People with CF

Research indicates that exercise may benefit people with CF by improving ion regulation in the airways,[9],[10] thereby increasing ASL height and
improving airway clearance, and by increasing growth hormone levels,[96] which may help to prevent decreased bone mineral density. Additionally,
based on studies with children and adolescents with CF, high-intensity intermittent exercise appears to be the optimal exercise intensity because it
has been shown to increase growth hormone levels while minimizing the inflammatory response.[96] Inflammation leads to muscle wasting and
decreased bone mineral density for people with CF,[96],[97],[100],[101],[102],[103],[104],[105] and so the risk of an exercise-induced inflammatory
response must be considered when initiating exercise interventions for this population. The effect of exercise on oxidative stress in people with CF
has not yet been researched. Theoretically, regular exercise may help to decrease oxidative stress over time,[10],[125] but the potential risk of
increasing oxidative stress with exercise must also be considered. During periods of high estrogen levels, exercise may help to offset the negative
effects of estrogen and improve Cl- secretion for females with CF.[138]

It should be noted that research on the cellular effects of exercise for people with CF is limited. Many of the exercise interventions used in the
existing research on this topic consist only of single bouts of exercise instead of long-term exercise programs. Also, most of the studies looking at
the inflammatory response to exercise included children and adolescents with CF, but not adults. Clearly, more research is needed to determine
the effects of regular exercise on cellular mechanisms in people of all ages with CF, as well as the impact of these cellular effects on functional
outcomes and disease progression. Future research should explore the effects of regular exercise over time on ion regulation in the airway
epithelial cells, inflammatory and growth hormone responses, and oxidative stress in people with CF. Additionally, the optimal exercise frequency,
intensity, and duration based on cellular effects should be further examined. While the effects of exercise on the animal models of CF have yet to
be researched, these models present an excellent opportunity for future research. Exercise research with the animal models could address a gap
in the literature by providing detailed information on the effects of long-term, regular exercise at the cellular and systemic levels, as well as the
impact of exercise on CF disease progression.

In conclusion, research has shown that exercise positively impacts functional and systemic outcomes in people with CF,[6],[7],[8] but research
regarding cellular level outcomes is lacking. While the research on functional outcomes provides evidence to support exercise interventions in this
population, it is important to understand the cellular effects of exercise to ensure the interventions do not cause damage or progression of the
disease. Research on cellular mechanisms is especially useful to determine the optimal type and intensity of exercise with respect to its risks and
benefits for this population. Although more research is needed, the available evidence indicates that high-intensity intermittent exercise may
maximize the benefits while minimizing the risks of exercise at the cellular level for people with CF.[96] As always, the clinician should consider the
individual needs of each patient and his or her response to the intervention when implementing these recommendations.

Click here to see a video demonstrating the impact of exercise on the life of one person with CF.

Bibliography
1. U.S. National Library of Medicine. (2011). Cystic Fibrosis. Retrieved January 23, 2012.
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001167/.
2. Cystic Fibrosis Foundation. (2011). About Cystic Fibrosis. Retrieved January 23, 2012. http://www.cff.org/AboutCF.
3. Grubb BR, Boucher RC. Pathophysiology of gene-targeted mouse models for cystic fibrosis. Physiological Reviews, 1999;79(1):S193-S214.
4. Dorin JR, Stevenson BJ, Fleming S, Alton EWFW, Dickinson P, Porteous DJ. Long-term survival of the exon 10 insertional cystic fibrosis mutant
mouse is a consequence of low level residual wild-type CFTR gene expression. Mamm Genome, 1994;5:465472.
5. Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh MJ. Expression of cystic
fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature,
1990;347:358363.
6. Schneiderman-Walker J, Pollock SL, Corey M, et al. A randomized controlled trial of a three year home exercise program in cystic fibrosis. J
Pediatr 2000; 136: 304310.
7. Salh W, Bilton D, Dodd M, Webb AK. Effect of exercise and physiotherapy in aiding sputum expectoration in adults with cystic fibrosis. Thorax.
1989;44(12):1006-1008.
8. Nixon PA, Orenstein DM, Kelsey SF, Doershuk CF. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med.
1992;327(15):1785-1788.
9. Wheatley CM, Wilkins BW, Snyder EM. Exercise is medicine in cystic fibrosis. Exerc Sport Sci Rev. 2011;39(3):155-160.
10. Cholewa JM, Paolone VJ. Influence of exercise on airway epithelia in cystic fibrosis: A review. Med Sci Sports Exerc. 2012.
11. Johns hopkins CF center | what is CF? | diagnosis | testing | nasal potential difference
http://www.hopkinscf.org/main/whatiscf/diag_testnasal.html. Accessed 3/1/2012, 2012.
12. Hebestreit A, Kersting U, Basler B, Jeschke R, Hebestreit H. Exercise inhibits epithelial sodium channels in patients with cystic fibrosis Am J
Respir Crit Care Med. 2001;164(3):443-446.
13. Schmitt L, Wiebel M, Frese F, et al. Exercise reduces airway sodium ion reabsorption in cystic fibrosis but not in exercise asthma Eur Respir J.
2011;37(2):342-348.
14. Chambers L, Rollins B, Tarran R. Liquid movement across the surface epithelium of large airways. Respir Physiol Neurobiol. 2007; 159 (3):
256-270.
15. Kallok MJ, Lai-Fook SJ, Hajji MA, Wilson TA. Axial distortion of airways in the lung. J Appl Physiol. 1983;54:185190.
16. Grygorczyk R, Hanrahan JW. CFTR-independent ATP release from epithelial cells triggered by mechanical stimuli. Am J Physiol
1997;272:C1058C1066.
17. Homolya L, Steinberg TH, Boucher RC. Cell to cell communication in response to mechanical stress via bilateral release of ATP and UTP in
polarized epithelia. J Cell Bio. 2000;150(6):1349-60.
18. Knight GE, Bodin P, De Groat WC, Burnstock G. ATP is released from guinea pig ureter epithelium on distension. Am J Physiol Renal Physiol
2002;282:F281F288.
19. Basser PJ, McMahon TA, Griffith P. The mechanism of mucus clearance in cough. J Biomech Eng. 1989;111:288297.
20. Button B, Picher M, Boucher RC. Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway
epithelia. J Physiol 2007;580:577592.
21. Grierson JP, Meldolesi J. Shear stress-induced [Ca2+]i transients and oscillations in mouse fibroblasts are mediated by endogenously released
ATP. J Biol Chem 1995;270:44514456.
22. Guyot A, Hanrahan JW. ATP release from human airway epithelial cells studied using a capillary cell culture system. J Physiol. 2002;545:199
206.
23. Lazarowski ER, Tarran R, Grubb BR, van Heusden CA, Okada S, Boucher RC. Nucleotide release provides a mechanism for airway surface
liquid homeostasis. J Biol Chem. 2004;279:3685536864.
24. Tarran R, Button B, Picher M, et al. Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral
infections. J Biol Chem.2005;280:35751-9.
25. Mitchell CH, Carre DA, McGlinn AM, Stone RA, Civan MM. A release mechanism for stored ATP in ocular ciliary epithelial cells. Proc Natl Acad
Sci U S A 1998;95:71747178.
26. Okada SF, Nicholas RA, Kreda SM, Lazarowski ER, Boucher RC. Physiological regulation of ATP release at the apical surface of human
airway epithelia. J Biol Chem. 2006;281:2299223002.
27. Button B, Boucher R. Role of mechanical stress in regulating airway surface hydration and mucus clearance rates. Respir Physiol Neurobiol.
2008;163(1-3):189-201.
28. Donaldson SH, Lazarowski ER, Picher M, Knowles MR, Stutts MJ, Boucher RC. Basal nucleotide levels,
release, and metabolism in normal and cystic fibrosis airways. Mol Med. 2000;6:969982.
29. Donaldson S, Bennett W, Zeman K, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. New Engl J Med. 2006;
354 (3): 241-250.
30. Lazarowski ER, Boucher RC, Harden TK. Mechanisms of release of nucleotides and integration of their
action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 2003;64:785795.
31. Hebestreit H, Kieser S, Junge S, Ballmann, Hebestreit A, Schindler C, Schenk T, Possett H, Kriemler S. Ling-term effects of a partially
supervised conditioning programme in cystic fibrosis. Eur Respir J. 2010; 35:578-583.
32. Selvadurai HC, Blimkie CJ, Meyers N, et al. Randomized controlled study of in-hospital exercise training programs in children with cystic
fibrosis. Pediatr Pulmonol 2002; 33: 194200.
33. Orenstein DM, Franklin BA, Doerchuk CF, et al. Exercise conditioning and cardiopulmonary fitness in cystic fibrosis. The effects of a three-
month supervised running program. Chest 1981; 80: 392398.
34. Moorcroft AJ, Dodd ME, Morris J, et al. Individualized unsupervised exercise training in adults with cystic fibrosis: a 1 year randomized
controlled trial. Thorax 2004; 59: 10741080.
35. Klijn PHC, Oushoorn A, van der Ent CK, et al. Effects of anaerobic training in children with cystic fibrosis: a randomized controlled study. Chest
2004; 125: 12991305.
36. Novaira H, Ornellas D, Ortiga-Carvalho T, Zhang X, Souza-Menezes J, Guggino S, Guggio W, Morales M. Atrial natriuretic peptide modulates
cystic fibrosis transmembrane conductance regulator chloride channel expression in rat proximal colon and human intestinal epithelial cells. J of
Endocrinol. 2006; 189: 155-165.
37. Dietz J. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J Physiol Regul Integr Comp Physiol. 1984; 247
R1093R1096.
38. Dietz J. Control of atrial natriuretic factor release from a rat heart-lung preparation. Am J Physiol Regul Integ Comp Physiol. 1987; 252 R498
R502.
39. Kelley TJ, Cotton CU, Drumm ML. Regulation of amiloride-sensitive sodium absorption in murine airway epithelium by C-type natriuretic
peptide. Am J Physiol (Lung Cell Mol Physiol) 1998;274:L990L996.
40. Olivera W, Ridge K, Wood LDH, Sznajder JL. ANF decreases active sodium transport and increases alveolar epithelial permeability in rats. J
Appl Physiol 1993;75:15811586.
41. DAngelis CA, Holm BA, Lakshminrusimha S, et al. Ontogeny of atrial natriuretic peptide and its receptor in the lung: effects on perinatal
surfactant release. Pediatr Res. 2008;63(3):239-244.
42. Dagnino L, Drouin J, Nemer M. Differential expression of natriuretic peptide genes in cardiac and extracardiac tissues. Mol Endocrinol. 1991;
5:12921300.
43. Gutkowska J, Tremblay J, Meyer R, Marcinkiewicz M, Nemer M. Evidence for atrial natriuretic peptide (ANP) synthesis and the presence of
ANP-transducing receptors in the rat olfactory bulb. J Neurochem. 1991; 57:18551861.
44. Gutkowska J, Cantin M, Genest J, Sirois P. Release of immunoreactive atrial natriuretic factor from the isolated perfused rat lung. FEBS Lett.
1987; 214:1720
45. Crozier IG, Nicholls MG, Ikram H, Espiner EA, Yandle TG, Jans S. Atrial natriuretic peptide in humans. Production and clearance by various
tissues. Hypertension. 1986; 8:II11II15
46. Kuhn M. Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase. A. Circ
Res.2003; 93:700709
47. Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate dependent signaling
functions. Endocr Rev. 2006; 27:4772.
48. Tremblay J, Desjardins R, Hum D, Gutkowska J, Hamet P. Biochemistry and physiology of the natriuretic peptide receptor guanylyl cyclases.
Mol Cell Biochem. 2002; 230:3147.
49. Argenzio RA & Armstrong M. ANP inhibits NaCl absorption and elicits Cl- secretion in porcine colon: evidence for cGMP and Ca2+ mediation.
Am J Physiol Regul Integr Comp Physiol. 1993; 265 R57R65.
50. Lin M, Nairn AC & Guggino SE 1992 cGMP-dependent protein kinase regulation of a chloride channel in T84 cells. Am J Physiol Regul Integr
Comp Physiol. 1992; 262 C1304C1312.
51. Campbell AR, Folkesson HG, Berthiaume Y, et al. Alveolar epithelial fluid clearance persists in the presence of moderate left atrial
hypertension in sheep. J Appl Phys. 1999; 86 (1): 139-151.
52. Hackney AC. Exercise as a stressor to the human neuroendocrine system. Medicina (Kaunas, Lithuania). 2006;42(10):788-97.
53. McMurray RG, Hackney AC. Endocrine responses to exercise and training. In: Garrett WE, Kirkendall DT, editors. Exercise and Sport Science.
Philadelphia (PA): Lippincott Williams &Wilkins; 2000. p. 135-56.
54. Goodman J, Logan A, McLaughlin P, et al. Atrial natriuretic peptide during acute and prolonged exercise in well-trained men. Int J Sports Med.
1993; 14: 185-190.
55. Mandroukas K, Zakas A, Aggelopoulou N, K. Atrial natriuretic factor responses to submaximal and maximal exercise. Brit Med.
1995;29(4):248-251.
56. Mandroukas A, Metaxas T, Heller J, Vamvakoudis E, Christoulas K, et al. The effect of different exercise-testing portocols on atrial natriuretic
peptide. Clin Physiol Funct Imaging. 2011; 31: 5-10.
57. Tamaoki J, Isono K, Kondo M, Yamawaki I, Tagava E, Nagai A. A human bronchial epithelial cell releases arginine vasopressin: involvement of
Ca2+-activated K+ channels. Regulatory peptides. 1998;74(2-3):91-95.
58. Wade CE. Response, regulation, and actions of vasopressin during exercise: a review. Med Sci Sports Exercise. 1984;16(5):506-511.
59. Langberg H, Bjorn C, Boushel R, Hellsten Y, Kjaer M. Exercise-induced increase in interstitial bradykinin and adenosine concentrations in
skeletal muscle and peritendinous tissue in humans. J Physiol. 2002;542(3):977-983.
60. Stebbins CL, Carretero OA, Mindroiu T, Longhurst JC. Bradykinin release from contracting skeletal muscle of the rat. J Appl Physiol.
1990;69(4):1225-1230.
61. Vettor R, Palo C De, Calo L, et al. Effect of exercise on plasma kallikrein and musclar phospholipase A2 activity in rats. Mol Cell Endocrinol.
1986;45(1):65-70.
62. Phillips YE, Yeates DB. Bidirectional transepithelial water transport: chloride-dependent mechanism. J Membr Biol. 2000;175(3):213-221.
63. Tamaoki J, Konda M, Takeuchi S, Takemura H, Nagai A. Vasopressin stimulates ciliary motility of rabbit tracheal epithelium: role of V1b
receptor-mediated Ca2+ mobilization. Am J Respir Cell Mol Biol. 1998;19(2):293-299.
64. Brooks G, Fahey T, Kenneth B. Is AMPK the metabolic master switch for energy-sensing metabolism in skeletal muscle? In: Exercise
Physiology: Human Bioenergetics. 4th ed. New York, NY: McGraw-Hill Inc Medical;2005;148-150.
65. Budinger GRS, URich D, DeBiase PJ, et al. Stretch-induced activation of AMP kinase in the lunge requires dystroglycan. Am J Respir Cell Mol
Biol. 2008;39(6):666-672.
66. Hallows KR, Fitch AC, Richardson CA, et al. Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane
conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation. J Biol Chem. 2006;281(7):4231-4241.
67. Spence HJ, Dhillon AS, James M, Winder SJ. Dystroglycan, a scaffold for the ERK-MAP kinase cascade. EMBO Rep. 2004;5(5):484-489.
68. Takawira D, Budinger GRS, Hopkinson SB, Jones JCR. A drystroglycan/plectin scaffold mediates mechanical pathway birfurcation in lung
epithelial cells. J Biol Chem. 2011;286(8):6301-6310.
69. Gusarova GA, Dada LA, Kelly AM, et al. Alpha1-AMP-activated protein kinase regulates hypoxia-induced Na2K-ATPase endocytosis via direct
phosphorylation of protein kinase C zeta. Mol Cell Biol. 2009;29(13):3455-3464.
70. Klein H, Garneau L, Trinh NTN, et al. Inhibition of the KCA3.1 channels in AMP-activated protein kinase in human airway epithelial cells. Am J
Physiol Cell Physiol. 2009;296(2):C285-295.
71. Mace OJ, Woollhead AM, Baines DL. AICAR activates AMPK and alters PIP2 association with the epithelial sodium channel ENaC to inhibit
Na+ transport in H441 lung epithelial cells. J Physiol. 2008;586(Pt 18): 4541-4557.
72. Hou X, Song J, Li XN, et al. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant
thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun. 2010;396(2):199-205.
73. Hwang JT, Kwon DY, Park OJ, Kim MS. Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes
Nutr. 2008;82(3):323-326.
74. Tsai KL, Chen LH, Chiou SH, et al. Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-
mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. Mol Nutr Food Res. 2006;127(5):591-604.
75. Myerburg MM, King JD, Oyster NM, et al. AMPK agonists ameliorate sodium and fluid transport and inflammation in cystic fibrosis airway
epithelial cells. Am J Respir Cell Mol Biol. 2010;42(6):676-684.
76. Woollhead AM, Scott JW, Hardie Dg, Baines DL. Phenformin and 5-aminoimidazole-4 carboxamide-1-beta-d-ribofuranoside (AICAR) activation
of AMP-activated protein kinase inhibits transepithelial Na+ transport across H441 lung cells. J Physiol. 2005;566:781-792.
77. Brown MB, McCarty NA, Millard-Stafford M. High-sweat Na+ in cystic fibrosis and healthy individuals does not diminish thirst during exercise in
the heat. Am J Physiol Regul Integr Comp Physiol.2011;301 (4): R1177-R1185.
78. Brown MB, Haack KKV, Pollack BP, Millard-Stafford M, McCarty NA. Low abundance of sweat duct Cl- channel CFTR in both healthy and
cystic fibrosis athletes with exceptionally salty sweat during exercise.Am J Physiol Regul Integr Comp Physiol.2011;300: R605R615.
79. Bar-Or O, Blimkie CJ, Hay JA, et al. Voluntary dehydration and heat intolerance in cystic fibrosis. Lancet 1992; 339:696699.
80. Potter L, Yoder A, Flora D, Antos L, Dickey D. Natriuretic peptides: their structures, receptors, physiologic functions, and therapeutic
applications. Handb Exp Pharmacol. 2009; 191: 342-366.
81. Ploeger HE, Takken T, de Greef MHG, Timmons BW. The effects of acute and chronic exercise on inflammatory markers in children and adults
with a chronic inflammatory disease: a systematic review. Exerc Immunol Rev, 2009;15:6-41.
82. Boas SR, Danduran MJ, McBride AL, McColley SA and O'Gorman MR. Postexercise immune correlates in children with and without cystic
fibrosis. Med Sci Sports Exerc, 2000;32:1997-2004.
83. Keller P, Keller C, Carey AL, Jauffred S, Fischer CP, Steensberg A, et al. Interleukin-6 production by contracting skeletal muscle autocrine
regulation by IL-6. Biochem Biophys Res Commun, 2003;310:550-554.
84. Penkowa M, Keller C, Keller P, Jauffred S, Pedersen BK. Immunohistochemical detection of interleukin-6 in human skeletal muscle fibres
following exercise. FASEB J, 2003;17:2166-2168.
85. Petersen AM and Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol, 2005;98:1154-1162.
86. Malm C. Exercise immunology: the current state of man and mouse. Sports Med, 2004;34(9):555-566.
87. Moldoveanu AI, Shephard RJ and Shek PN. Exercise elevates plasma levels but not gene expression of IL-1beta, IL-6, and TNF-alpha in blood
mononuclear cells. J Appl Physiol, 2000;89:1499-1504.
88. Pedersen BK and Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev, 2000;80:1055-
1081.
89. Suzuki K, Nakaji S, Yamada M, Totsuka M, Sato K and Sugawara K. Systemic inflammatory response to exhaustive exercise. Cytokine
kinetics. Exerc Immunol Rev, 2002;8:6-48.
90. Woods J, Lu Q, Ceddia MA and Lowder T. Special feature for the Olympics: effects of exercise on the immune system: exercise-induced
modulation of macrophage function. Immunol Cell Biol, 2000;78:545-553.
91. Gleeson M. Immune function in sport and exercise. J Appl Physiol, 2007;103:693-699.
92. King DE, Carek P, Mainous AG, III and Pearson WS. Inflammatory markers and exercise: differences related to exercise type. Med Sci Sports
Exerc, 2003;35:575-581.
93. Bruunsgaard H. Physical activity and modulation of systemic low-level inflammation. J Leukoc Biol, 2005;78:819-835.
94. Gokhale R, Chandrashekara S and Vasanthakumar KC. Cytokine response to strenuous exercise in athletes and non-athletesan adaptive
response. Cytokine, 2007;40:123-127.
95. Pedersen BK and Saltin B. Evidence for prescribing exercise as therapy in chronic disease. Scandinavian Journal of Medicine Science in
Sports, 2006;16(Suppl 1):3-63.
96. Nguyen T, et al. Inflammatory and growth factor response to continuous and intermittent exercise in youth with cystic fibrosis. J Cyst Fibros,
2011;doi:10.1016/j.jcf.2011.10.001.53.
97. Ionescu AA, Mickleborough TD, Bolton CE, Lindley MR, Nixon LS, Dunseath G, Luzio S, Owens DR, Shale DJ. The systemic inflammatory
response to exercise in adults with cystic fibrosis. J Cyst Fibros, 2006;5(2):105-112.
98. Street ME, Spaggiari C, Volta C, Ziveri MA, Viani I, Rossi M, Pisi G, Grzincich G, Bernasconi S. The IGF system and cytokine interactions and
relationships with longitudinal growth in prepubertal patients with cystic fibrosis. Clin Endocrinol, 2009;70(4):593-598.
99. Saadane A, Soltys J, Berger M. Role of IL-10 deficiency in excessive nuclear factor- activation and lung inflammation in cystic fibrosis
transmembrane conductance regulator knockout mice. J Allergy Clin Immunol, 2005;115(2)405-411.
100. Ionescu AA, Nixon LS, Evans WD, Stone MD, Lewis-Jenkins V, Chatham K, Shale DJ. Bone density, body composition, and inflammatory
status in cystic fibrosis. Am J Respir Crit Care Med, 2000;162(3 Pt 1):789-794.
101. Ionescu AA, Nixon LS, Luzio S, Lewis-Jenkins V, Evans WD, Stone MD, et al. Pulmonary function, body composition and protein catabolism
in adults with cystic fibrosis. Am J Respir Crit Care Med, 2002;165:495-500.
102. Aris RM, Renner JB Winders AD, Buell HE, Riggs DB, Lester GE, et al. Increased rate of fractures and severe kyphosis: sequelae of living
into adulthood with cystic fibrosis. Ann Intern Med, 1998;128:186-193.
103. Haworth CS, Selby PL, Webb AK, Martin L, Elborn JS, Sharpless LD, et al. Inflammatory related changes in bone mineral content in adults
with cystic fibrosis. Thorax, 2004;59:613-617.63.
104. Tirakitsoontorn P, Nussbaum E, Moser C, Hill M, Cooper DM. Fitness, acute exercise and anabolic and catabolic mediators in cystic fibrosis.
Am J Respir Crit Care Med, 2001;168:1476-1480.64.
105. Tiao G, Hoblet S, Wang JJ, Meyer TA, Luchetter FA, Fischer JE, et al. Sepsis is associated with increased mRNAs of the ubiquitin
proteasome porteolytic pathway in human skeletal muscle. J Clin Invest, 1997;99:163-168.
106. Moeller A, Stampfli SF, Rueckert B, Rechsteiner T, Hamacher J, Wildhaber JH. Effects of a short-term rehabilitation program on airway
inflammation in children with cystic fibrosis. Pediatr Pulmonol, 2010;45:541-551.
107. Boas SR, Danduran MJ, McColley SA, Beaman K, OGorman MRG. Immune modulation following aerobic exercise in children with cystic
fibrosis. Int J Sports Med, 2000;21:294-301.
108. Shmarina GV. Pukhalsky AL, Kokarovtseva SN, Pukhalskaya DA, Shabalova LA, Kapranov NI, Kashirskaja NJ. Tumor necrosis factor-
alpha/interleukin-10 balance in normal and cystic fibrosis children. Mediators Inflamm. 2001;10(4):191-197.
109. Boas SR, Danduran MJ, McBride AL, McColley SA, OGorman MRG. Posteexercise immune correlates in children with and without cystic
fibrosis. Medicine & Science in Sports & Exercise, 2000;32(12):1997-2004.
110. Sahlberg M, Svantesson U, Magnusson Thomas E, Andersson BA, Saltin B, Strandvik B. Muscular strength after different types of training in
physically active patients with cystic fibrosis. Scand J Med Sci Sports. 2008;18(6):756-764.
111. Gleeson M, Bishop N, Oliveira M, Tauler P. Influence of training load on upper respiratory tract infection incidence and antigen-stimulated
cytokine production. Scand J Med Sci Sports, 2011;Epub ahead of print.
112. Nemet D, Eliakim A. Growth hormone-insulin-like growth factor-1 and inflammatory response to a single bout in children and adolescents.
Medicine and Sport Science, 2010;55:141-155.
113. Pedersen B, Febbraio M. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev, 2008;88:1379-1406.
114. J. Paccou, N. Zeboulon, C. Combescure, L. Gossec, and B. Cortet. The prevalence of osteoporosis, osteopenia, and fractures among adults
with cystic fibrosis: a systematic literature review with meta-analysis. Calcif Tissue Int. 2010; 86 (1): 17.
115. Gore A, Ho Kwon S, Stenbit A. A roadmap to the brittle bones of cystic fibrosis. J of Osteoporos. 2011: 1-10.
116. De Martinis M, Di Benedetto MC, Mengoli LP, Ginaldi L. Senile osteoporosis: Is it an immune-mediated disease? Inflamm Res. 2006 Oct;
55(10): 399-404.
117. Garcia S, Sanchez M, Cejudo P, Gallego E, Dapena J, Jimenez R, Luis P, Gomez de Terreros I. Bone health, daily physical activity, and
exercise tolderance in patients with cystic fibrosis. Chest. 2001; 140: 475-481.
118. Haworth CS, Selby PL, Webb AK, et al. Low bone mineral density in adults with cystic fibrosis. Thorax. 1999;54:9617.
119. Sermet-Gaudelus I, Castanet M, Retsch-Bogart G, Aris R. Update on cystic-fibrosis-related bone disease: a special focus on children.
Paediatr Respir Rev. 2009; 10 (3): 134-142.
120. Velsor LW, Kariya C, Kachadourian R, Day BJ. Mitochondrial oxidative stress in the lungs of cystic fibrosis transmembrane conductance
regulator protein mutant mice. Am J Respir Cell Mol Biol. 2006;35(5):579-586.
121. Kelly-Aubert M, Trudel S, Fritsch J, et al. GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models. Hum Mol Genet.
2011;20(14):2745-2759.
122. Antigny F, Girardin N, Raveau D, Frieden M, Becq F, Vandebrouck C. Dysfunction of mitochondria Ca2+ uptake in cystic fibrosis airway
epithelial cells. Mitochondrion. 2009;9(4):232-241.
123. Preiser JC. Oxidative stress. JPEN J Parenter Enteral Nutr. 2012;36(2):147-154.
124. Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: A 30 year history. Dyn Med. 2009;8:1.
125. Falone S, Mirabilio A, Pennelli A, et al. Differential impact of acute bout of exercise on redox- and oxidative damage-related profiles between
untrained subjects and amateur runners. Physiol Res. 2010;59(6):953-961.
126. Radak Z, Chung HY, Koltai E, Taylor AW, Goto S. Exercise, oxidative stress and hormesis. Ageing Res Rev. 2008;7(1):34-42.
127. Hollander J, Fiebig R, Gore M, Ookawara T, Ohno H, Ji LL. Superoxide dismutase gene expression is activated by a single bout of exercise in
rat skeletal muscle. Pflugers Arch. 2001;442(3):426-434.
128. Hemmrich K, Suschek CV, Lerzynski G, Kolb-Bachofen V. iNOS activity is essential for endothelial stress gene expression protecting against
oxidative damage. J Appl Physiol. 2003;95(5):1937-1946.
129. Ji LL, Gomez-Cabrera MC, Vina J. Exercise and hormesis: Activation of cellular antioxidant signaling pathway. Ann N Y Acad Sci.
2006;1067:425-435.
130. Radak Z, Chung HY, Goto S. Systemic adaptation to oxidative challenge induced by regular exercise. Free Radic Biol Med. 2008;44(2):153-
159.
131. Ceolotto G, Gallo A, Papparella I, et al. Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-
dependent mechanism. Arterioscler Thromb Vasc Biol. 2007;27(12):2627-2633.
132. Demko, C.A., Byard, P.J., and Davis, P.B. 1995. Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection. J. Clin. Epidemiol.
48:10411049.
133. Block, J.K., et al. 2006. Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria. Thorax.
61:969974
134. Rosenfeld, M., Davis, R., FitzSimmons, S., Pepe, M.,and Ramsey, B. 1997. Gender gap in cystic fibrosis mortality. Am. J. Epidemiol.
145:794803.
135. Kaza, V., Katz, M.F., Cumming, S., Frost, A.E., and Safdar, Z. 2007. Correlation of chest radiograph pattern with genotype, age, and gender in
adult cystic fibrosis: a single-center study. Chest. 132:569574.
136. Zeitlin PL: Cystic fibrosis and estrogens: a perfect storm. J Clin Invest 2008, 118:3841-3844.
137. Hartzell C, Putzier I, Arreola J. Calcium-activated chloride channels. Annu Rev Physiol. 2005; 67:71958.
138. Coakley, R.D., et al. 2008. 17b-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid
volume in human cystic fibrosis airway epithelia. J. Clin. Invest. 118:40254035.
139. Morley, P., Whitfield, J.F., Vanderhyden, B.C., Tsang, B.K., and Schwartz, J.L. 1992. A new, nongenomic estrogen action: the rapid release of
intracellular calcium. Endocrinology. 131:13051312.
140. Haynes, M.P., Russell, K.S., and Bender, J.R. 2000. Molecular mechanisms of estrogen actions on the
vasculature. J. Nucl. Cardiol. 7:500508.
141. Le Mellay, V., Lasmoles, F., and Lieberherr, M. 1999. Galpha(q/11) and gbetagamma proteins and membrane signaling of calcitriol and
estradiol. J. Cell Biochem. 75:138146.
142. Goodstadt, L., Powell, T., and Figtree, G.A. 2006. 17beta-estradiol potentiates the cardiac cystic fibrosis transmembrane conductance
regulator chloride current in guinea-pig ventricular myocytes. J. Physiol. Sci. 56:2937.
143. Rochwerger, L., and Buchwald, M. 1993. Stimulation of the cystic fibrosis transmembrane regulator expression by estrogen in vivo.
Endocrinology.133:921930.

Go To Cystic Fibrosis Cell Bio Page

Return To Welcome Page

Comments
Hide All Comments Unfold All Fold All
page 1 of 2 1 2 next

Susan Wilson 12 Jan 2012, 07:47 Fold

.
Last edited on 11 Mar 2012, 11:22 by Susan Wilson Show more
Reply Options

PTXXIV 4 Mar 2012, 09:48 Fold

I'm offended! lol

Reply Options

Emily Offenberger 29 Feb 2012, 17:52 Fold

Great pictures for the TEP section! Great work Megan!

Reply Options

JennyKohr 6 Mar 2012, 22:28 Fold

This exercise page is coming along really well! You all are doing a great job of synthesizing the exercise effects and applying it to CF. I really
enjoyed reading the sex related differences and exercise section and learning about the inhibitory role that estrogen plays on calcium activation!
The pictures also really help to clarify information!

Reply Options

Scott Sheaffer 7 Mar 2012, 16:12 Fold

I like the layout when you list "Study 1" and then its important info and then "Study 2" and its important info. I would suggest keeping a consistent
format though. When reading the page I wondered why I only found this layout at 2 points on the page. Overall, I think your page is informative
and demonstrates hard work.

Reply Options

Sarah Hendershot 7 Mar 2012, 17:53 Fold

Thanks for the suggestion Scott! We really appreciate you reading our page and providing us with constructive feedback. The varied
format in the presentation of the literature is likely due to the varied amount and type of information available on each topic. We will look
into this suggestion as we begin editing the page and try to make the format as consistent as possible.

Reply Options

Lynn Krimmer 7 Mar 2012, 17:03 Fold

Like others have said, this page is coming along really well! I think the use of pictures in the beginning of the page are helpful to walk through the
process of determining the nasal potential difference. I also like the use of tables in the inflammatory section to help break up the large amount of
information.

Reply Options

DR Ebner 9 Mar 2012, 14:41 Fold

I know this page is mostly based on cellular responses to exericse, but I was wondering if there was any increases in VO2 in people with CF who
exercise and if that alters their symptoms. If there is an increase in VO2 would you know if it is due to improved lung function, decrease
inflammation, or improvement in oxygen utilization in the mitochondira similar to healthy subjects when exercising. I think the page looks very
good.

Reply Options

Sarah Hendershot 9 Mar 2012, 15:38 Fold

DR, thanks for bringing up this point! Yes, there is evidence to show that exercise improves more functional and body systems outcomes,
including VO2 max and pulmonary functionwhich is huge for this population! There is even one study that followed a group of people
with CF for 8 years and found that higher aerobic capacity at the beginning of the study was associated with a lower risk of dying
throughout the study period. We will briefly address these outcomes in the introduction. For the purposes of this page, our main goal is to
show how exercise affects people with CF at the cellular level to determine the optimal exercise intensity, as well as the risk vs benefits of
exercise in terms of disease progression. (However, we found a big gap in the literature. As you can see from the page, there is very
limited research on the effects of regular exercise on cellular mechanisms in people with CF.)

Reply Options

Cara Whalen 9 Mar 2012, 17:52 Fold

Yes, and to piggyback off of Sarah, in the studies that I looked at where inflammation either increased or did not change in
response to exercise VO2 increased with exercise training. So from that limited research, it would appear that improved VO2max is
somewhat independent of inflammatory responses. As I think it should be, because in healthy individuals, it is normal to have
increased inflammation with exercise and yet people are still capable of improving their VO2 max. But perhaps, VO2max would
improve more with less of an inflammatory response (as in with trained athletes). But I am not aware of any studies that specifically
look at this, and I certainly did not run across this in my research for CF.

Reply Options

nsmith5232 10 Mar 2012, 00:22 Fold

nice job handeling the conflicting research, it is hard to recommend exercise when either two studies totally disagree, or there is no clear
evidence of studies on humans with a particular disease looking at the cell factor you are describing. Sometimes it is nice to look at the bigger
picture when recommending exercise and make justifications based on those studies. sweet page though, someone is definately a syntax master.

Last edited on 10 Mar 2012, 00:23 by nsmith5232 Show more

Reply Options

Emily L Smith 10 Mar 2012, 12:12 Fold

Like Scott said, I like how you present your studies 1 and 2 in the beginning. The format is really easy to read and understand. It would be helpful
to have more studies in similar format. I also like that you have an implications and recommendations section after most types of exercise. Good
work!

Reply Options

Megan Vandrak 10 Mar 2012, 13:32 Fold

Thank you both Emily and Scott for the suggestions! By default I had to put my study 1 and study 2 into sort of a list format because I was
unable to make a list/bullet items in a table hence the difference in format amongst all the difference studies. If anyone knows how to put
bullets or lists in a table, please let me know! :-)

Reply Options

Megan B 10 Mar 2012, 12:35 Fold

Overall, I think this page looks really good. You might want to consider using consistent subheadings (implications and recommendations) for
each section throughout the page. Nice job with Figures 1 and 2!

Reply Options

Kara Armstrong 11 Mar 2012, 09:04 Fold

I think your group did a good job analyzing the studies critically (talking about studies validity and the negative aspects of the study). Also I love
the addition of the video at the end. It puts a face with your page and shows us it is possible to train at high levels regardless!
 Reply Options

Alyssa Meyer 11 Mar 2012, 12:06 Fold

I'm glad you watched the video Kara! It really is inspirational!

Reply Options

page 1 of 2 1 2 next
Add a New Comment

Go To Cystic Fibrosis Cell Bio Page

Return To Welcome Page

page revision: 281, last edited: 12 Mar 2012, 00:01 (1911 days ago)
Edit Tags History Files Print Site tools + Options

Powered by Wikidot.com Help | Terms of Service | Privacy | Report a bug | Flag as objectionable

Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License