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Basic Sciences-The Human Body - The Respiratory

Basic Sciences-The Human Body - The Respiratory

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Chronic obstructive pulmonary disease (COPD) is a
progressive respiratory disease characterized by the

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combination of signs and symptoms of emphysema and
bronchitis. It is a common disease, and each year about
30,000 people in the United Kingdom and roughly
119,000 people in the United States die from COPD.
Sources of noxious particles that can cause COPD include
tobacco smoke, air pollution, and the burning of certain
fuels in poorly ventilated areas. In rare cases COPD has
been associated with a genetic defect that results in def-
ciency of alpha-1 antitrypsin. Although primarily a lung
disease, it is increasingly recognized that COPD has sec-
ondary associations, including muscle weakness and
osteoporosis. Identifying and treating these secondary
problems via pulmonary rehabilitation (supervised exer-
cise) and other methods may improve the functional
status of the lungs.
COPD is distinguished pathologically by the destruc-
tion of lung tissue, which is replaced by holes characteristic
of emphysema, and by a tendency for excessive mucus
production in the airway, which gives rise to symptoms of
bronchitis. These pathological characteristics are realized
physiologically as diffculty in exhaling (called fow limita-
tion), which causes increased lung volume and manifests
as breathlessness. Other early symptoms of the condition
include a “smoker’s cough” and daily sputum production.
Coughing up blood is not a feature of COPD and when
present raises concern about a second, tobacco-related
condition, particularly lung cancer. Patients with COPD
are vulnerable to episodic worsening of their condition
(called exacerbation). Exacerbations are triggered by
infection, either bacterial or viral. Therefore, antibiotics,
which work against bacteria, are not always required.
Frequent exacerbations, particularly if severe enough to
warrant hospital admission, indicate a poor prognosis.
The only therapeutic intervention shown to alter the
course of COPD is removal of the noxious trigger, which

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can be accomplished in most cases by cessation of smok-
ing. Treatments used in the early stages of disease include
vaccination against infuenza and pneumococcal pneu-
monia and administration of drugs that widen the
airways (i.e., bronchodilators). Inhaled corticosteroids
are commonly prescribed, especially for patients with
frequent exacerbations. Short courses (typically fve
days) of oral corticosteroids are given for exacerbations
but generally are not used in the routine management of
COPD. A six- to eight-week course of pulmonary reha-
bilitation often benefts patients who have symptoms
despite inhaler therapy. This should be followed by a
community/home maintenance program or by repeat
courses every two years.
In COPD patients with low blood–oxygen levels, the
prescription of home oxygen can reduce hospital admis-
sion and extend survival but does not alter the progression
of lung disease. Some COPD patients do not fnd oxygen
attractive, since they need to use it for 16 hours each day
to derive beneft, which leads to further diffculties in
mobility. In addition, oxygen is extremely fammable, and
the prescription of oxygen for patients who smoke remains
controversial because of the risk for explosion. Specialized
centres can offer treatments for patients with advanced
disease, including noninvasive ventilation and surgical
options (i.e., lung transplantation and lung-volume
reduction).

Lung Congestion

Lung congestion is characterized by distention of blood
vessels in the lungs and flling of the alveoli with blood as a
result of an infection, high blood pressure, or cardiac
insuffciencies (i.e., inability of the heart to function ade-
quately). Active congestion of the lungs is caused by

139

infective agents or irritating gases, liquids, and particles.
The alveolar walls and the capillaries in them become dis-
tended with blood. Passive congestion is due either to
high blood pressure in the capillaries, caused by a cardiac
disorder, or to relaxation of the blood capillaries followed
by blood seepage.

Left-sided heart failure—inability of the left side of
the heart to pump suffcient blood into the general circu-
lation—causes back pressure on the pulmonary vessels
delivering oxygenated blood to the heart. The blood pres-
sure becomes high in the alveolar capillaries, and they
begin to distend. Eventually the pressure becomes too
great, and blood escapes through the capillary wall into
the alveoli, fooding them. Mitral stenosis, narrowing of
the valve between the upper and lower chambers in the
left side of the heart, causes chronic passive congestion.
Iron pigment from the blood that congests the alveoli
spreads throughout the lung tissue and causes deteriora-
tion of tissue and formation of scar tissue. The walls of the
alveoli also thicken and gas exchange is greatly impaired.
The affected person shows diffculty in breathing, there is
a bloody discharge, and the skin takes on a bluish tint as
the disease progresses.
Passive congestion caused by relaxation of the blood
vessels occurs in bedridden patients with weak heart
action. Blood accumulates in the lower part of the lungs,
although there is usually enough unaffected lung tissue for
respiration. The major complication arises in mild cases of
pneumonia, when the remaining functioning tissue
becomes infected.
Pulmonary edema is much the same as congestion
except that the substance in the alveoli is the watery
plasma of blood, rather than whole blood, and the
precipitating causes may somewhat differ. Infammatory
edema results from infuenza or bacterial pneumonia. In

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X-ray showing lung congestion caused by congestive heart failure. Dr.
Thomas Hooten/Centers for Disease Control and Prevention (CDC)
(Image Number: 6241)

141

mechanical edema the capillary permeability is broken
down by the same type of heart disorders and irritants as
in congestion. It can occur, for unknown reasons, after
reinfation of a collapsed lung. After an operation, if too
great a volume of intravenous fuids is given, the blood
pressure rises and edema ensues. Excessive irradiation and
severe allergic reactions may also produce this disorder.
The lungs become pale, wet, enlarged, and heavy. It
may take only one or two hours for two to three quarts of
liquid to accumulate. Acute cases can be fatal in 10 to 20
minutes. A person with pulmonary edema experiences dif-
fculty in breathing, with deep gurgling rattles in the
throat. The person’s skin turns blue, and, because he or
she is too weak to clear the fuids, the person may actually
drown in the lung secretions.

Atelectasis

Atelectasis is characterized primarily by the absence of air
in the lungs. The term is derived from the Greek words
atele¯s and ektasis, literally meaning “incomplete expansion”
in reference to the lungs. The term atelectasis can also be
used to describe the collapse of a previously infated lung,
either partially or fully, because of specifc respiratory dis-
orders. There are three major types of atelectasis: adhesive,
compressive, and obstructive.
Adhesive atelectasis is seen in premature infants who
are unable to spontaneously breathe and in some infants
after only a few days of developing breathing diffculties;
their lungs show areas in which the alveoli, or air sacs, are
not expanded with air. These infants usually suffer from a
disorder called respiratory distress syndrome, in which
the surface tension inside the alveolus is altered so
that the alveoli are perpetually collapsed. This is typically
caused by a failure to develop surface-active material

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X-ray showing changes in the right upper pulmonary lung feld that are
characteristic of atelectasis. Dr. Thomas Hooten/Centers for Disease
Control and Prevention (CDC) (Image Number: 6242)

143

(surfactant) in the lungs. Treatment for infants with this
syndrome includes replacement therapy with surfactant.
Compressive atelectasis is caused by an external pres-
sure on the lungs that drives the air out. Collapse is
complete if the force is uniform or is partial when the
force is localized. Local pressure can result from tumour
growths, an enlarged heart, or elevation of the diaphragm.
The ducts and bronchi leading to the alveoli are squeezed
together by the pressure upon them.
Obstructive atelectasis may be caused by foreign
objects lodged in one of the major bronchial passage-
ways, causing air trapped in the alveoli to be slowly
absorbed by the blood. It may also occur as a complica-
tion of abdominal surgery. The air passageways in the
lungs normally secrete a mucous substance to trap dust,
soot, and bacterial cells, which frequently enter with
inhaled air. When a person undergoes surgery, the anes-
thetic stimulates an increase in bronchial secretions.
Generally, if these secretions become too abundant, they
can be pushed out of the bronchi by coughing or strong
exhalation of air. After abdominal surgery, the breathing
generally becomes more shallow because of the sharp
pain induced by the breathing movements, and the mus-
cles beneath the lungs may be weakened. Mucous plugs
can result that cause atelectasis. Other causes of obstruc-
tion include tumours or infection.
The symptoms in extreme atelectasis include low blood
oxygen content, which manifests as a bluish tint to the skin,
absence of respiratory movement on the side involved,
displacement of the heart toward the affected side, and
consolidation of the lungs into a smaller mass. If a lung
remains collapsed for a long period, the respiratory tissue is
replaced by fbrous scar tissue, and respiratory function can-
not be restored. Treatment for obstructive and compressive

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atelectasis is directed toward removal of any obstruction or
compressive forces.

Lung Infarction

Lung infarction is the death of one or more sections
of lung tissue due to deprivation of an adequate blood
supply. The section of dead tissue is called an infarct. The
cessation or lessening of blood fow results ordinarily from
an obstruction in a blood vessel that serves the lung. The
obstruction may be a blood clot that has formed in a dis-
eased heart and has traveled in the bloodstream to the
lungs, or air bubbles in the bloodstream (both of these are
instances of embolism), or the blockage may be by a clot
that has formed in the blood vessel itself and has remained
at the point where it was formed (such a clot is called a
thrombus). Ordinarily, when the lungs are healthy, such
blockages fail to cause death of tissue because the blood
fnds its way by alternative routes. If the lung is congested,
infected, or inadequately supplied with air, however, lung
infarctions can follow blockage of a blood vessel.
Because neither the lung tissue nor the pleural sac sur-
rounding the lungs has sensory endings, infarcts that occur
deep inside the lungs produce no pain; those extending to
the outer surface cause fuids and blood to seep into the
space between the lungs and the pleural sac. The sac dis-
tends with the excess fuid and there may be diffculty in
infating the lungs. When pain is present it indicates pleu-
ral involvement. The pain may be localized around the rib
cage, shoulders, and neck, or it may be lower, near the
muscular diaphragm that separates the chest cavity from
the abdomen. One explanation for the pain is that it is
from tension on the sensitive nerve endings in the mem-
brane lining the chest. Pain is most severe on inhalation.

145

The symptoms of infarcts are generally spitting up of
blood, coughing, fever, moderate diffculty in breathing,
increased heartbeat, pleural rubbing, diminished breath
sounds, and a dull sound heard when the chest is tapped.
The blood shows an increase in number of white blood
cells and sedimentation rate (clumping of red blood cells).
Infarcts that do not heal within two or three days gener-
ally take two to three weeks to heal. The dead tissue is
replaced by scar tissue.

Cystic Fibrosis

Cystic fbrosis, also known as mucoviscidosis, is an inher-
ited metabolic disorder, the chief symptom of which is the
production of a thick, sticky mucus that clogs the respira-
tory tract and the gastrointestinal tract. Cystic fbrosis
was not recognized as a separate disease until 1938 and was
then classifed as a childhood disease because mortality
among afficted infants and children was high. However,
by the mid-1980s, more than half of all victims of cystic
fbrosis survived into adulthood owing to aggressive ther-
apeutic measures.

Cystic fbrosis is an inherited disorder mainly affect-
ing people of European ancestry. It is estimated to occur
in 1 per 2,000 live births in these populations and is par-
ticularly concentrated in people of northwestern European
descent. It is much less common among people of African
ancestry (about 1 per 17,000 live births) and is very rare in
people of Asian ancestry. The disorder was long known to
be recessive (i.e., only persons inheriting a defective gene
from both parents will manifest the disease). The disease
has no manifestations in heterozygotes (i.e., those indi-
viduals who have one normal copy and one defective copy
of the particular gene involved). However, when both

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parents are heterozygous, they may expect that, on the
basis of chance, one out of four of their offspring will have
the disease. In 1989 the defective gene responsible for cys-
tic fbrosis was isolated. The gene, called cystic fbrosis
transmembrane conductance regulator, or CFTR, lies in
the middle of chromosome 7 and encodes a protein of the
same name, designated CFTR.
Cystic fbrosis affects the functioning of the body’s
exocrine glands (e.g., the mucus-secreting and sweat
glands) in the respiratory and digestive systems. Within
the cells of the lungs and gut, the CFTR protein trans-
ports chloride across cell membranes and regulates other
channels. These functions are critical for maintaining and
adjusting the fuidity of mucous secretions. Most cases of
cystic fbrosis are caused by a mutation that corresponds
to the production of a CFTR protein that lacks the amino
acid phenylalanine. As a result, chloride and sodium ions
accumulate within cells, thereby drawing fuid into the
cells and causing dehydration of the mucus that normally
coats these surfaces. The thick, sticky mucus accumulates
in the lungs, plugging the bronchi and making breathing
diffcult. This results in chronic respiratory infections,
often with Staphylococcus aureus or Pseudomonas aeruginosa.
Chronic cough, recurrent pneumonia, and the progressive
loss of lung function are the major manifestations of lung
disease, which is the most common cause of death of per-
sons with cystic fbrosis.
In the digestive system, the abnormally thick mucous
secretions interfere with the passage of digestive enzymes
and thus block the body’s absorption of essential nutri-
ents. The resulting maldigestion and malabsorption of
food can cause affected individuals to become malnour-
ished despite an adequate diet. Bulky, greasy, foul-smelling
stools are often the frst signs of cystic fbrosis. About 10

147

percent of infants with cystic fbrosis have intestinal
obstruction at birth due to very thick secretions. In addi-
tion, mutations in the CFTR gene are associated with
degeneration of the ductus deferens and sterility in adult
males who have cystic fbrosis.
Cystic fbrosis causes the sweat glands to produce
sweat that has an abnormally high salt content. The high
salt content in perspiration is the basis for the “sweat
test,” which is the defnitive diagnostic test for the pres-
ence of cystic fbrosis. Mutations associated with cystic
fbrosis can be detected in screening tests. These tests are
effective in the identifcation of adult carriers (heterozy-
gotes), who may pass a mutation on to their offspring, as
well as in the identifcation of newborns who may be at
risk for the disorder.
The treatment of cystic fbrosis includes the intake of
pancreatic enzyme supplements and a diet high in calo-
ries, protein, and fat. Vigorous physical therapy on a daily
basis is used to loosen and drain the mucous secretions
that accumulate in the lungs. Medications such as dornase
alfa, a recombinant form of the enzyme deoxyribonucle-
ase, are given to thin mucus, facilitating its clearance from
the lungs through coughing. In addition, bronchodilators
can be used to relax the smooth muscles that line the air-
ways and cause airway constriction, making it easier for
patients to breathe. These agents may be administered by
means of an inhaler or a nebulizer, which is powered by a
compressor that sprays aerosolized drug into the airways.
The anti-infammatory agent ibuprofen has been shown
to slow the deterioration of lung tissue in some cystic
fbrosis patients. In severe cases, lung transplantation may
be considered. Many patients with cystic fbrosis regularly
take antibiotics, sometimes in aerosolized form, in order
to fght lung infections.

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Among the most promising treatments under inves-
tigation for cystic fibrosis is gene therapy. Gene therapy
first emerged as a potential form of treatment in 1990,
when researchers successfully restored CFTR chloride
channel function in cultured lung and airway epithelial
cells that carried CFTR mutations. The researchers
used recombinant DNA technology to generate viral
vectors containing normal copies of the CFTR gene.
These vectors were then transfected into the cultured
cells, which subsequently incorporated the normal
genes into their DNA. This success led to the first clini-
cal trial of gene therapy for cystic fibrosis in 1993. The
same technology was used to insert the CFTR gene into
a replication-deficient adenovirus that was then admin-
istered into the noses and lungs of patients. This first
trial initially appeared to be successful, since increased
expression of the CFTR protein was observed shortly
after treatment. However, the patients experienced
severe side effects, including lung inflammation and
signs of viral infection. Since the 1990s, gene therapy
for cystic fibrosis has undergone significant refine-
ment, and the outcomes of clinical trials are marked by
steady improvement. However, the natural defense sys-
tems of the lungs and airways have proved significant
obstacles to cellular uptake of the viral vector carrying
the normal CFTR gene. As a result, the development of
an effective gene delivery system has become a major
focus of cystic fibrosis gene therapy. Delivery systems
under investigation include cationic polymer vectors,
cationic liposomes, and adenovirus associated virus.
The latter, which can bind to a type of receptor
expressed in high numbers on the surfaces of lung cells,
has proved particularly effective in laboratory studies
using human lung tissue.

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