Background on Lung Disease

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Background on Lung Disease
The function of the lung is to excrete CO2 from
blood and replenish O2 The chest wall and
diaphragm allow air to move in and out of the
lungs thus allowing gas exchange across the
alveolocapillary membrane Organize lung disease
into those affecting 1- the airways 2- the
interstitium 3- the pulmonary vascular
system In addition to the lungs, the respiratory
system also includes 1- the diaphragm and the
muscles of the chest wall 2- the regulatory
neural circuits 3- the pleural spaces 4- the
upper respiratory tract (nasopharynx and trachea
including the larynx)
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ATELECTASIS (COLLAPSE)
Fig. 1 It is loss of lung volume due to
inadequate expansion of airspaces It is divided
into 1- Resorption Atelectasis when an
obstruction prevents air from reaching distal
airways ? collapse of adjacent lung. Often
involves obstruction of a bronchus by a mucus
(bronchial asthma, bronchiectasis, chronic
bronchitis). Obstruction is caused by aspiration
of foreign bodies (children), blood clots
(surgery, anesthesia), tumors, enlarged lymph
nodes (tuberculosis) 2- Compression Atelectasis
associated with accumulations of fluid, blood or
air within the pleural cavity ? collapse of
adjacent lung. Such accumulations are often seen
in congestive heart disease and pneumothorax
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ATELECTASIS (COLLAPSE)
Fig. 2 3- Microatelectasis is a generalized loss
of expansion mainly due to loss of surfactant
(non-obstructive atelectasis). Present in adult
and neonatal respiratory distress syndromes as
well as lung diseases associated with
interstitial inflammation 4- Contraction
Atelectasis occurs when either local or
generalized fibrotic changes in the lung hamper
expansion and increase elastic recoil during
expiration Atelectasis (except that caused by
contraction) is potentially reversible
4
Obstructive and Restrictive Lung Diseases
Pulmonary Diseases can be divided 1-
Obstructive Diseases (airway diseases) ?
limitation of airflow due to partial or complete
obstruction at any level 2- Restrictive Diseases
characterized by reduced expansion of lung
parenchyma ? decreased total lung
capacity Obstructive Diseases include 1)
asthma, 2) emphysema, 3) chronic bronchitis, 4)
bronchiectasis, 5) cystic fibrosis and 6)
bronchiolitis Hallmark is decreased expiratory
flow rate due to expiratory obstruction either
from anatomic airway narrowing (asthma) or loss
of elastic recoil (emphysema) Restrictive
Diseases include 1) Adult Respiratory Distress
Syndrome, and 2) Chronic Restrictive Diseases
such as sarcoidosis and idiopathic pulmonary
fibrosis Expiratory flow rate is normal but the
restrictive defect occurs in 2 conditions a)
extrapulmonary disorders that affect the
respiratory muscles and b) acute or chronic
interstitial lung diseases
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Obstructive Lung DiseasesAsthma

• GENERAL BACKGROUND
• Believed to result from persistent bronchial
  inflammation ? considered a chronic inflammatory
  disorder of the airways
• Clinically manifested by episodic dyspnea, cough
  and wheezing
• Disease affects 5 of adults and 7-10 of
  children

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Obstructive Lung DiseasesAsthma (cont)

• GENERAL BACKGROUND (cont)
• Classified into 2 major categories
• 1- Extrinsic asthma consisting of three types
  a) atopic asthma (most common type with an onset
  in first 2 decades of life), b) occupational
  asthma and c) allergic bronchopulmonary
  aspergillosis (bronchial colonization with
  Aspergillus organisms followed by development of
  IgE antibodies)
• 2- Intrinsic asthma in which triggering
  mechanisms are non-immune. A number of stimuli
  are involved a) pulmonary viral infections, b)
  cold, c) psychological stress, d) exercise,
  irritant inhalation (sulfur dioxide)

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Obstructive Lung DiseasesAsthma (cont)

• PATHOGENESIS
• Common denominator underlying all forms of
  asthma is an increased airway reactivity to a
  variety of stimuli
• Bronchial hyperresponsiveness can be demonstrated
  due to bronchial inflammation ? manifested by
  presence of inflammatory cells ? damage to the
  bronchial epithelium ? consistent feature of
  bronchial asthma
• What causes bronchial inflammation?
• In allergic or atopic asthma is explained by
  type I hypersensitivity reactions but the cause
  is much less clear in patients with so called
  intrinsic asthma

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ATOPIC ASTHMA
Fig. 2 During type I hypersensitivity reactions
? sensitization of TH2 lymphocytes ? release of
cytokines (IL-4 and IL-5) ? synthesis of IgE,
growth of mast cells (IL-4), and growth and
activation of eosinophils (IL-5) IgE, mast cells
and eosinophils are key players in allergic
asthma Attacks of atopic asthma demonstrate two
phases 1) early phase (30-60 min after
inhalation of antigen) followed by 2) 4-8h more
prolonged late phase Initial triggering of mast
cells on the mucosal surface ? release of variety
of primary and secondary mediators such as 1)
Leukotrienes C4, D4, E4, 2) Prostaglandin D2, 3)
Eosinophilic and Neutrophilic Chemotactic Factors
and Leukotriene B4, and 4) Platelet-Activating
Factor ? induction of bronchoconstriction, edema,
mucus secretion ? additional recruitment of
leukocytes (basophils, neutrophils, and
eosinophils)
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INTRINSIC ASTHMA
Initial triggering by respiratory viral
infections and inhaled air pollutants (sulfur
dioxide, ozone, nitrogen dioxide) ? Increased
airway hyperreactivity in both normal and
asthmatic subjects ? In asthmatics, the
bronchial response is much more severe and
sustained. In these patients, bronchial
hyperresponsiveness is superimposed on clinically
manifest chronic bronchitis referred to as
chronic asthmatic bronchitis
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CLINICAL COURSE OF ASTHMA
Attack of asthma is characterized by severe
dyspnea with wheezing (difficulty in
expiration) ? Patient labors to get air into
the lungs and then cannot get it
out ? Progressive hyperinflation of the lungs
with air trapped distal to the bronchi, which are
constricted and filled with mucus and
debris ? Attacks last from 1h to several
hours. Medication involves the use of
bronchodilators and corticosteroids ? Interval
s between attacks are free from respiratory
difficulty but persistent respiratory deficits
can be detected by spirometric methods ? The
associated hypercapnia, acidosis, and severe
hypoxia can be fatal although the disease is more
disabling than lethal
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CHRONIC OBSTRUCTIVE PULMONARY DISEASES
Objective evidence of persisting and
irreversible airflow obstruction Others use the
term COPD more broadly to include 1- Chronic
Bronchitis 2- Emphysema By the time these
patients develop sufficient dyspnea
(breathlessness), they seek medical attention at
which time airway obstruction can be
diagnosed Most often, these two conditions
co-exist
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EMPHYSEMA
Characterized by permanent enlargement of the
airspace distal to the terminal bronchioles
accompanied by destruction of their walls The
relation between chronic bronchitis and emphysema
is complicated with emphysema being a morphologic
one whereas chronic bronchitis is defined on the
basis of clinical features like presence of
chronic and recurrent cough with excess mucus
secretion. The two diseases usually coexist
because the major pathogenic mechanism (cigarette
smoke) is common to both. Types of emphysema
involve 1- Centriacinar 2- Panacinar 3-
Distal Acinar The first two are more important
but their differentiation is difficult when the
disease is advanced
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EMPHYSEMA (cont)
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EMPHYSEMA (cont)

• Two of the recognized causes are smoking and
  inherited a1-antitrypsin deficiency
• Hereditary a1-antitrypsin deficiency is more
  common in young persons with emphysema
• Most common in persons of Scandinavian descent,
  and is rare in Jews, blacks, and Japanese
• Homozygotes (who carry two defective genes) have
  about 15-20 of normal plasma concentration of
  a1-antitrypsin deficiency

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EMPHYSEMA (cont)
Fig. 4 Pathogenesis includes -The most
plausible hypothesis to explain alveolar wall
destruction and airspace enlargement invokes
excess protease or elastase activity unopposed by
appropriate anti-protease regulation -In
general, impaction of smoke particles leads in
the influx of neutrophils and macrophages, both
of which secrete elastase -An increase in the
elastase activity localized in the centriacinar
region, together with the smoke-induced decrease
of a1-antitrypsin activity causes the
centriacinar pattern of emphysema seen in smokers
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EMPHYSEMA (cont)

• Almost all persons who have emphysema before the
  age of 40 years have a1-antitrypsin deficiency
• Smoking and repeated respiratory tract infections
  (both contribute to decreased a1-antitrypsin
  levels) contribute to the risk of emphysema in
  persons with an a1-antitrypsin deficiency
• Laboratory methods exist for measuring
  a1-antitrypsin levels
• Recombinant human a1-antitrypsin is available as
  a replacement therapy in persons with the
  hereditary deficiency of the enzyme

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EMPHYSEMA (cont)
Fig. 3 Its precise incidence is difficult to
estimate because its definite diagnosis (based on
morphology) can be made only by lung autopsy It
is present in about 50 of adults who come to
autopsy Centriacinar emphysema is much more
common in and severe in men than in women A
clear association between cigarette smoking and
emphysema with the most severe type occurring in
heavy smokers Becomes disabling during the fifth
to eight decades of life
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EMPHYSEMA (cont)
Fig. 5 Clinical course includes -Dyspnea is
usually the first symptom and it is steadily
progressive -Weight loss is common and be so
severe as to suggest a hidden malignancy -The
classic presentation in individuals with no
bronchitic component is one in which the
patient is barrel-chested and dyspneic, with
obviously prolonged expiration, sitting forward
in a hunched-over position, attempting to squeeze
the air out of the lungs with each expiratory
effort -On the other extreme are patients with
emphysema and pronounced chronic bronchitis with
less prominent dyspnea and respiratory drive so
they retain carbon dioxide
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CHRONIC BRONCHITIS
GENERAL BACKGROUND -Common among cigarette
smokers -Some studies of men in the 40- to
65-year age group indicate that 20 to 25 have
the disease -Chronic bronchitis is defined as a
persistent productive cough for at least 3
consecutive months in at least two consecutive
years -It can occur in several forms 1-Simple
Chronic Bronchitis 2-Chronic Mucopurulent
Bronchitis (sputum contains pus due to secondary
infections)
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20 min BREAK
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CHRONIC BRONCHITIS
GENERAL BACKGROUND (cont) 3-Chronic Asthmatic
Bronchitis (hyperresponsive airways and
intermittent episodes of asthma) 4-Chronic
Obstructive Bronchitis (development of chronic
outflow obstruction) -Morphogenic basis of
airflow obstruction is twofold 1-Inflammation,
fibrosis and resultant narrowing of
bronchioles (small airway disease) 2-Coexis
tent emphysema
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CHRONIC BRONCHITIS (cont)
Fig. 6 Pathogenesis includes -The distinctive
feature is hypersecretion of mucus that starts in
the large airways -Although the most important
causative factor is smoking, other air pollutants
(sulfur dioxide an nitrogen dioxide) may also
contribute -These irritants induce
hypersecretion of the bronchial mucous glands,
cause hypertrophy of the mucous glands and lead
to metaplastic formation of mucin-secreting
goblet cells in the surface epithelium of
bronchi -Microbial infection plays a secondary
role by maintaining the inflammation and
exacerbating symptoms
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CHRONIC BRONCHITIS (cont)
CLINICAL COURSE -A prominent cough and the
production of sputum may persist indefinitely
without ventilatory dysfunction -Some patients
develop significant COPD with outflow obstruction
which is further accompanied by hypercapnia,
hypoxemia and in severe cases, cyanosis -With
progression, chronic bronchitis is complicated by
cardiac failure -Recurrent infections and
respiratory failure are constant threats
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BRONCHIECTASIS
Fig. 7 Permanent dilation of bronchi and
bronchioles due to destruction of the muscle and
elastic supportive tissue, resulting from or
associated with chronic necrotizing
infections -Not a primary disease but rather
secondary to persisting infection or obstruction
caused by a Variety of conditions -Conditions
predisposing include 1-Bronchial obstruction by
tumors, foreign bodies, mucus impaction 2-Congen
ital or hereditary conditions including cystic
fibrosis, immunodeficiency states, Kartageners
syndrome 3-Necrotizing pneumonia complicating
measles, whooping cough and influenza
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BRONCHIECTASIS (cont)
PATHOGENESIS -Two processes are
critical 1-Obstruction 2-Chronic persistent
infection -Either of these two processes may
come first. Normal clearance mechanisms are
hampered by obstruction, so secondary infection
soon follows -Conversely, chronic infection
causes damage to bronchial walls leading to
weakening and dilation
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BRONCHIECTASIS (cont)
CLINICAL COURSE -Clinical manifestations consist
of severe, persistent cough -Sputum may contain
flecks of blood and frank hemoptysis may
occur -Clubbing of the fingers may develop -In
cases of severe, widespread bronchiectasis,
significant obstructive ventilatory defects
develop with hypoxemia, hypercapnia and pulmonary
hypertension
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RESTRICTIVE LUNG DISEASES
-Characterized by reduced compliance since more
pressure is required to expand the lungs because
they are stiff -Two general features of
restrictive pulmonary diseases 1- Only a thin
basement membrane and the cytoplasm of two very
flat cells (endothelium and alveolar epithelium)
are interposed between air and blood. The
initiating injury in these diseases usually
affects either of these two cell types although
with chronicity changes in the interstitium tend
to dominate. Because of that, these disorders are
often referred to as interstitial lung
disease 2- Fibrosis produces a stiff lung
which in turn reduces lung compliance and
necessitates increased effort of breathing
(dyspnea). Damage to the alveolar epithelium and
interstitial vasculature leads to hypoxia because
of abnormalities in the ventilation/perfusion
ratio
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RESTRICTIVE LUNG DISEASES (cont)
Fig. 8 -Restrictive lung diseases can be
either 1-Acute associated with pulmonary edema
often with accompanying inflammation 2- Chronic
associated with respiratory dysfunction due to
chronic inflammation and fibrosis
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ACUTE RESTRICTIVE LUNG DISEASES(ARDS)
-Adult Respiratory Distress Syndrome (ARDS) is
characterized by acute onset of respiratory
distress accompanied by 1-Decreased arterial
oxygen pressure 2-Decreased lung
compliance 3-Development of diffuse pulmonary
infiltrates -Diffuse alveolar damage is the
morphologic feature of ARDS and is associated
with diffuse alveolar endothelial and epithelial
injury and usually pulmonary edema
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ARDS (cont)
Table 1 -Compelling evidence that neutrophils
and most likely macrophages are involved
in mediating the injury in most
cases -Collectively, the consequences of
all mediators and reactions involved are
1) interstitial edema and 2) necrosis
of endothelial and epithelial cells
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ARDS (cont)
Fig. 9 Clinical course involves -Mortality is
about 50 -The more severe the initial
permeability leak in alveolorcapillary membranes,
the poorer the diagnosis -A cofounding clinical
problem is that the high levels of oxygen
sometimes used to treat hypoxemia may lead to
additional alveolar damage due to oxygen
toxicity -Alveolar exudates provide a rich
culture medium for microorganisms and
consequently secondary infections -Patients who
survive the acute insult, normal respiratory
function returns within 4-6 months
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CHRONIC RESTRICTIVE LUNG DISEASES
Table 2 -These disorders account for about 15
of non- infectious diseases -They can be divided
to 1-those with known causes 2-those of unknown
causes 3-and further divided on the basis of
presence or absence of granulomas -This
distinction is of some utility when diagnosis is
made from biopsy tissue
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IDIOPATHIC PULMONARY FIBROSIS
Fig. 10 -Idiopathic Pulmonary Fibrosis (IPF)
refers to a poorly understood pulmonary disorder
of unknown cause characterized histologically by
diffused interstitial fibrosis which in advanced
cases results in severe hypoxemia and
cyanosis -Males are affected more often than
females and most patients are between 30 and 50
years old when the condition is
diagnosed -Proposed sequence of events begins
with alveolar wall injury resulting in
interstitial edema and accumulation of
inflammatory cells (alveolitis)
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IDIOPATHIC PULMONARY FIBROSIS (cont)
Fig. 11 -In general, IPF is initiated by
unknown injurious agents that cause alveolitis
and also induce an immune response. -Intra-alveol
ar inflammation causes epithelial cell injury and
triggers a fibrogenic response in which
lymphocytes, macrophages, and type II pneumocytes
all participate -Clinically patients exhibit
respiratory difficulty and in advanced cases,
hypoxemia and cyanosis -The median survival is
about 5 years
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SARCOIDOSIS
GENERAL BACKGROUND -A multisystem disease of
unknown cause characterized by noncaseating
granulomas in many tissues and organs -It occurs
worldwide but the frequency varies in different
populations. In the USA, it occurs in 1 to 4 per
10,000 and is 10 times more prevalent in blacks
-The disease represents a cell-mediated immune
response to an unidentified antigen -Many causal
agents have been proposed at the immunogen
(atypical mycobacteria) but none has been proved
to be the cause
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SARCOIDOSIS
GENERAL BACKGROUND (CONT) -The disease is
entirely asymptomatic and only discovered on
routine chest films or as an incidental finding
at autopsy. However, in about two thirds of
symptomatic cases there is gradual appearance of
respiratory symptoms (shortness of breath, cough)
or constitutional signs and symptoms (fever,
fatigue, weight loss, anorexia, night
sweats) -Overall, 65-70 of affected patients
recover with minimal manifestations. Twenty
percent develop permanent lung dysfunction or
visual impairment. Of the remaining 10-15 most
progress to pulmonary fibrosis
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SARCOIDOSIS (cont)
Fig. 12 -Findings below are consistent with a
cell-mediated immune response 1- Most patients
manifest cutaneous anergy to common skin test
antigens to which normal persons have been
exposed and sensitized 2-Number of peripheral
blood T lymphocytes is often decreased resulting
in lymphopenia and the CD4 to CD8 ratio is less
than 0.8 (normal is 0.9-2.5) 3-In
bronchoalveolar lavage fluids there is an
increased number of T lymphocytes with a CD4 to
CD8 ratio of up to 101 4-Circulating B cells
are normal in number but the serum contains
excess polyclonal immunoglobulins