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Evaluating Respiratory Muscle Adaptations: A New Approach

Article  in  American Journal of Respiratory and Critical Care Medicine · January 2003

DOI: 10.1164/rccm.2209001 · Source: PubMed

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1418 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 166 2002
suppressive status found in the peripheral blood allows the
host to avoid a systemic inflammatory process? The authors
have nicely demonstrated a profound influence of the envi-
ronmental milieu on circulating monocytes and established a
direct link between plasma factors and HLA-DR expression.
Although there is no doubt that this marker of immunosup-
pression correlates with severe infection and poor outcome,
it remains unclear how the downregulation of this marker is
associated with poor outcome.
Jean-Marc Cavaillon, Dr.Sc.
UP Cytokines and Inflammation
Institut Pasteur
Paris, France
References
1. Pasteur L. De l’extension de la théorie des germes à l’étiologie de quel-
ques maladies communes. C R Acad Sci (Paris) 1880;90:1033–1044.
2. Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H, Dayer J-M.
Imbalance between tumour necrosis factor alpha and soluble TNF re-
ceptor concentrations in severe meningococcaemia. Immunology 1992;
76:20–23.
3. Marchand A, Devière J, Byl B, De Groote D, Vincent J-L, Goldman
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C, Fraisse F, Dinh-Xuan AT, Carli P, Spaulding C, et al. Successful
cardiopulmonary resuscitation after cardiac arrest as a “sepsis like”
syndrome. Circulation 2002;106:562–568.
5. Muñoz C, Carlet J, Fittin C, Misset B, Bleriot J-P, Cavaillon J-M. Disregu-
Evaluating Respiratory Muscle Adaptations
A New Approach
In this issue of AJRCCM (pp. 1491–1497), Ramı́rez-Sar-
miento and colleagues (1) present the results of a controlled
study of inspiratory muscle training that was performed in
patients with severe chronic obstructive pulmonary disease
(COPD). The experimental group of patients with COPD
received training by breathing through an inspiratory thresh-
old load for 30 minutes 5 days a week for 5 weeks. For each
subject, the load was set at 40–50% of the maximal inspiratory
pressure. This training protocol is best viewed as containing
both strength and endurance components. Control subjects
with COPD underwent sham therapy by breathing through
the same apparatus—without the load—as the experimental
group; the training schedule for the control group was identi-
cal to that of the experimental group. After training, the
experimental group exhibited increases in both inspiratory
muscle strength and endurance, whereas these measurements
did not change in the control group. Despite these improve-
ments in inspiratory muscle performance, exercise tolerance
did not improve.
This study by Ramı́rez-Sarmiento and coworkers (1) con-
tains additional important data that are novel and unique.
Before inspiratory muscle training and after its completion,
they obtained biopsies of the external intercostal muscles
from the fourth interspace in the anterior axillary line. In
this location, the serratus anterior muscle fibers lie superficial
to the external intercostals, and the internal intercostal fibers
lie deep to the external intercostals; nonetheless, the authors
present persuasive arguments that they are obtaining selec-
tive biopsies of the external intercostal. After training, the
experimental group exhibited increases in the proportion of
lation of in vitro cytokine production by monocytes during sepsis. J
Clin Invest 1991;88:1747–1754.
6. Prins JM, Kuijper EJ, Mevissen MLCM, Speelman P, van Deventer
SJH. Releases of tumor necrosis factor alpha and interleukin-6 during
antibiotic killing of Escherichia coli in whole blood: influence of antibi-
otic class, antibiotic concentration, and presence of septic serum. Infect
Immun 1995;63:2236–2242.
7. Majetschak M, Flach R, Heukamp T, Jennissen V, Obertacke U, Neudeck
F, Schmit-Neuerburg KP, Schade FU. Regulation of whole blood tu-
mor necrosis factor production upon endotoxin stimulation after se-
vere blunt trauma. J Trauma 1997;43:880–887.
8. Brandtzaeg P, Osnes L, Ovstbo R, Joo GB, Westvik A-B, Kierulf P. Net
inflammatory capacity of human septic shock plasma evaluated by a
monocyte-based target cell assay: identification of interleukin-10 as a
major functional deactivator of human monocytes. J Exp Med 1996;
184:51–60.
9. Fumeaux T, Pugin J. Role of interleukin-10 in the intracellular sequestra-
tion of human leukocyte antigen-DR in monocytes during septic shock.
Am J Respir Crit Care Med 2002;166:1475–1482.
10. Livingston DH, Appel SH, Wellhausen SR, Sonnenfeld G, Polk HC.
Depressed interferon gamma production and monocytes HLA-DR
expression after severe injury. Arch Surg 1988;123:1309–1312.
11. Lin RY, Astiz ME, Saxon JC, Rackow EC. Altered leukocyte immuno-
phenotypes in septic shock. Studies of HLA-DR, CD11b, CD14, and
IL-2R expression. Chest 1993;104:847–853.
12. Manjuck J, Saha DC, Astiz M, Eales LJ, Rackow EC. Decrease response
to recall antigens is associated with depressed costimulatory receptor
expression in septic critically ill patients. J Lab Clin Med 2000;135:153–
160.
13. Hensler T, Hecker H, Heeg K, Heidecke CD, Bartels H, Barthlen W,
Wagner H, Siewert J-R, Holzmann B. Distinct mechanism of immuno-
suppression as a consequence of major surgery. Infect Immun 1997;65:
2283–2291.
DOI: 10.1164/rccm.2209003
slow (type I) fibers and decreases in the proportion of fast
(type II) fibers; in addition, both fiber types exhibited an
increase in cross-sectional area, but only the increase in type
II fibers was statistically significant. All of these measure-
ments in the control group showed no differences between
pretraining and post-training biopsy specimens. Therefore,
the data indicate that the changes in the experimental group
represent adaptations elicited by the training, and they are
consistent with a training effect (2, 3). To the best of our
knowledge, these data represent the first longitudinal (i.e.,
changes over time in the same subject) histochemical evi-
dence of a human respiratory muscle training effect.
These adaptations warrant comment. We hypothesize that
the training-induced increase in the proportion of type I fibers
resulted from an endurance training effect on “decondi-
tioned” muscle; space constraints prevent elaboration of this
concept. In contrast, the increases in fiber-type cross-sec-
tional area are best explained as usual responses to strength-
training protocols (2, 3).
We have previously hypothesized that chronic endurance
training accounts for the diaphragmatic adaptations noted
in severe COPD. In contrast to the experimental design of
Ramirez-Sarmiento and coworkers, we (4, 5) and others (6,
7) have studied adaptations of the diaphragm to severe
COPD by comparing diaphragmatic features in groups of
subjects with minimal or no airways obstruction—control
groups—with those noted in groups of patients with severe
COPD. The term “cross-sectional approach” is applied to
this type of experimental design. We (4, 5) and others (6, 7)
have noted that severe COPD elicits the following diaphrag-
Editorials
matic adaptations: (1 ) a fast-to-slow transformation in myo-
sin heavy chain isoforms and important myofibrillar regula-
tory proteins (myosin light chains, troponin subunits, and
tropomyosins), (2 ) an increase in the proportion of type I
fibers (to levels that are above any “control data” in the
literature) and an accompanying decrease in the proportion
of type II fibers, (3 ) statistically significant decreases in the
cross-sectional area of slow (type I fibers) and a tendency of
type II fibers to show a decrease in cross-sectional area, (4 )
marked increases in the diaphragmatic area fraction of type
I fibers (the relative contribution of type I fibers to the cross-
sectional area of the diaphragm) and an accompanying de-
crease in the area fraction of type II fibers, (5 ) increases
in mitochondrial volume density, and (6 ) increases in the
mitochondrial oxidative capacity of all fiber types. Despite
this relative plethora of data on diaphragmatic remodeling
exhibited by patients with severe COPD, the cross-sectional
design of these studies does not allow definitive evaluation
of our hypothesis that diaphragmatic training accounts for
these adaptations.
We compare the training effect noted by Ramı́rez-Sar-
miento and coworkers (1) in the external intercostals with
our data on diaphragmatic adaptations exhibited by patients
with severe COPD. First, both the diaphragm and external
intercostal show an increase in the proportion of type I fibers.
The increase in the proportion of type I fibers reported by
Ramı́rez-Sarmiento and coworkers (1), however, was not
accompanied by any change in the relative contribution of
type I fibers to the cross-sectional area of the external inter-
costal (in the region of the biopsy), whereas the increase in
the proportion of type I fibers in the diaphragms of our
patients with severe COPD was accompanied by marked
increases in the area fraction of type I fibers.
How does one explain these differences between the adap-
tations of the diaphragm and the external intercostal? Con-
ceptually, our major point is that diaphragmatic myofibers
are working against the increased load of COPD for 24 hours
a day. We presume that this increased activity has gone on
for many years, and therefore, the remodeling—that we and
others have described—represents chronic adaptations (8).
In contrast, based on the available data in the literature
(reviewed in 9), we presume that the external intercostals—in
the region biopsied by Ramı́rez-Sarmiento and coworkers
(1)—are not active or only occasionally active during resting
breathing; however, when an external respiratory load—such
as that as that used by Ramı́rez-Sarmiento and coworkers
(1)—is superimposed on the increased airway load of COPD,
we hypothesize that the external intercostal myofibers in the
region of the biopsies are recruited for the duration of each
training interval and that this recruitment accounts for the
histologic features of the training effect seen in the post-
training biopsy. Therefore, after cessation of training—if the
severity of the COPD and respiratory muscle recruitment
pattern remain “essentially the same” in the patients of Ramı́-
Pulmonary Langerhans Cell Histiocytosis
What Was the Question?
Pulmonary Langerhans cell histiocytosis (LCH) has been
with us for over fifty years. In 1951 Farinacci and colleagues
reported two adult patients with “eosinophilic granuloma”
of the lungs (1). Six years later, Auld detailed microscopic
characteristics of LCH in lung biopsies from five patients
and in the process laid the foundation for all subsequent
histopathologic studies of this condition (2). In nearly five
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1419
rez-Sarmiento and coworkers—we hypothesize that these
training effects will not persist.
In conclusion, using cross-sectional comparisons, respira-
tory muscle biologists have learned much about the adapta-
tions of the respiratory muscles to severe COPD. This cross-
sectional approach, however, cannot provide us with informa-
tion about the effect of various therapeutic interventions
(training, lung volume reduction surgery, lung transplanta-
tion) on cellular and molecular adaptations in the respiratory
muscles. A longitudinal experimental design—similar to that
used by Ramı́rez-Sarmiento and coworkers (1)—would be
ideal to answer these questions. However, we must be certain
regarding the safety of the biopsy techniques used in this
longitudinal approach.
Sanford Levine, M.D.
Taitan Nguyen, B.S.E.
Larry R. Kaiser, M.D.
Joseph B. Shrager, M.D.
University of Pennsylvania Medical Center
Department of Veterans Affairs Medical Center
Philadelphia, Pennsylvania
References
1. Ramı́rez-Sarmiento A, Orozco-Levi M, Güell R, Barreiro E, Hernandez
N, Mota S, Sangenis M, Broquetas JM, Casan P, Gea J. Inspiratory
muscle training in patients with chronic obstructive pulmonary disease:
structural adaptation and physiologic outcomes. Am J Respir Crit Care
Med 2002;166:1491–1497.
2. Bell GJ, Syrotuik D, Martin TP, Burnham R, Quinney HA. Effect of
concurrent strength and endurance training on skeletal muscle proper-
ties and hormone concentrations in humans. Eur J Appl Physiol 2000;
81:418–427.
3. McCarthy JP, Pozniak MA, Agre JC. Neuromuscular adaptations to
concurrent strength and endurance training. Med Sci Sports Exerc
2002;34:511–519.
4. Levine S, Kaiser L, Leferovich J, Tikunov B. Cellular adaptations in the
diaphragm in chronic obstructive pulmonary disease. N Engl J Med
1997;337:1799–1806.
5. Levine S, Gregory C, Nguyen T, Shrager J, Kaiser L, Rubinstein N,
Dudley G. Bioenergetic adaptation of individual human diaphragmatic
myofibers to severe COPD. J Appl Physiol 2002;92:1205–1213.
6. Mercadier JJ, Schwartz K, Schiaffino S, Wisnewsky C, Ausoni S, Heim-
burger M, Marrash R, Pariente R, Aubier M. Myosin heavy chain
gene expression changes in the diaphragm of patients with chronic
lung hyperinflation. Am J Physiol 1998;274:L527–L534.
7. Orozco-Levi M, Gea J, Lloreta JL, Felez M, Minguella J, Serrano S,
Broquetas JM. Subcellular adaptation of the human diaphragm in
chronic obstructive pulmonary disease. Eur Respir J 1999;13:371–378.
8. Levine S, Nguyen T, Shrager JB, Kaiser L, Camasamudram V, Rubinstein
N. Diaphragm adaptations elicited by severe chronic obstructive pul-
monary disease: lessons for sports science. Exerc Sport Sci Rev 2001;
29:71–75.
9. De Troyer A. Relationship between neural drive and mechanical effect
in the respiratory system. Adv Exp Med Biol 2002;508:507–514.
DOI: 10.1164/rccm.2209001
decades since his careful and elegant description surprisingly
little has been added to our understanding of the basic micro-
scopic features of LCH. In this issue of AJRCCM, Dr. Kam-
bouchner and coworkers (pp. 1483–1490) (3) report morpho-
logic observations first published in preliminary form a
decade ago (4). The authors studied serial histologic sections
of 36 lesions captured in 12 surgical specimens from seven