Chapter 15: Lung: Obstructive versus Restrictive Pulmonary Diseases Flashcards Preview

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Flashcards in Chapter 15: Lung: Obstructive versus Restrictive Pulmonary Diseases Deck (128):

Based on pulmonary function tests, chronic noninfectious diffuse pulmonary diseases can be
classified in one of two categories:



  1. (1) obstructive diseases (or airway diseases)
  2. (2) restrictive diseases,


What are is an obstructive disease ( airway dse)?

(1) obstructive diseases (or airway diseases), characterized
by an increase in resistance to airflow due to partial or complete obstruction at any level, from
the trachea and larger bronchi to the terminal and respiratory bronchioles


What is restrictive dse?

(2) restrictive
diseases, characterized by reduced expansion of lung parenchyma and decreased total lung


In individuals with diffuse obstructive disorders, pulmonary function tests show
decreased maximal airflow rates
during forced expiration, usually measured by ___________

forced expiratory
volume at 1 second.


Expiratory airflow obstruction may be caused by a variety of conditions listed in Table 15-3 .

They are distinguished by _________ and hence different mechanisms for airflow obstruction.

As discussed below, such neat distinctions are not always

distinct anatomic lesions


In contrast, restrictive diseases are identified by a reduced total lung capacity, and an
expiratory flow rate that is normal or reduced proportionately.


Restrictive defects occur in two
general conditions:

 (1) chest wall disorders (e.g., neuromuscular diseases such as poliomyelitis, severe obesity, pleural diseases, and kyphoscoliosis) and

(2) chronic interstitial and infiltrative diseases, such as pneumoconioses and interstitial fibrosis of unknown etiology.


TABLE 15-3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic
Obstructive Pulmonary Disease

      Clinical Term :Anatomic Site


  • Chronic bronchitis : Bronchus
  • Bronchiectasis :Bronchus
  • Asthma : Bronchus
  • Emphysema: Acinus
  • Small-airway disease, bronchiolitis :Bronchiole


TABLE 15-3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic
Obstructive Pulmonary Disease



  • Anatomic Site: Bronchus
  • Major Pathologic Changes:  Mucous gland hyperplasia, hypersecretion
  • Etiology: Tobacco smoke, air
  • S/Sx: Cough, sputum production


TABLE 15-3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic
Obstructive Pulmonary Disease



Anatomic Site: Bronchus
Major Pathologic Changes:  Airway dilation and

Etiology: Persistent or severe

S/Sx: Cough, sputum production


TABLE 15-3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic
Obstructive Pulmonary Disease


Anatomic Site: Bronchus
Major Pathologic Changes:  Smooth muscle
hyperplasia, excess
mucus, inflammation

Etiology:Immunological or
undefined causes

S/Sx: Cough, sputum production


TABLE 15-3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic
Obstructive Pulmonary Disease



Anatomic Site: Acinus
Major Pathologic Changes:  Airspace enlargement; wall

Etiology:Tobacco smoke
S/Sx: Dyspnea


TABLE 15-3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic
Obstructive Pulmonary Disease



Anatomic Site: Bronchiole
Major Pathologic Changes: Inflammatory
Etiology:Tobacco smoke, air pollutants, miscellaneous
S/Sx:Cough, dyspnea


What is COPD?

Emphysema and chronic bronchitis are often clinically grouped together and referred to as
chronic obstructive pulmonary disease (COPD), since many patients have overlapping features
of damage at both the acinar level (emphysema) and bronchial level (bronchitis), almost
certainly because one extrinsic trigger—cigarette smoking—is common to both


In addition,
small-airway disease, a variant of chronic bronchiolitis, is now known to contribute to obstruction both in emphysema and chronic bronchitis.


[11] While asthma is distinguished from chronic
bronchitis and emphysema by the
presence of reversible bronchospasm, some patients with
otherwise typical asthma also develop an irreversible component (


Q image thumb

FIGURE 15-5 Schematic representation of overlap between chronic obstructive lung


some patients with otherwise typical COPD have a reversible component. It is clinically common
to label such patients as having COPD/asthma. In a recent study the overlap between these
three disorders was found to be substantial


In most patients, COPD is the result of long-term ____________

heavy cigarette smoking; about 10% of
patients are nonsmokers.


However, only a minority of smokers develop COPD, the
reason for which is still unknown


What is emphysema?

Emphysema is a condition of the lung characterized by irreversible enlargement of the
airspaces distal to the terminal bronchiole, accompanied by destruction of their walls without
obvious fibrosis




There is a clear-cut association between heavy cigarette
smoking and emphysema, and women and African Americans are more susceptible than other




How is emphysema classified?

Emphysema is classified according to its anatomic distribution within the lobule


Types of Emphysema.

Recall that the
lobule is a cluster of acini, the terminal respiratory units.


Although the term emphysema is
sometimes loosely applied to diverse conditions, there are four major types:



  • (1) centriacinar ,
  • (2) panacinar ,
  • (3) paraseptal, and
  • (4) irregular .

Of these, only the first two cause clinically significant airflow obstruction ( Fig. 15-6 ). 


Among the types of emphysema, which among the four causes clinically
significant airflow obstruction


(1) centriacinar ,

(2) panacinar


Centriacinar emphysema is far more common than
the panacinar form, constituting more than 95% of cases.


Q image thumb

FIGURE 15-6 Major patterns of emphysema.

A, Normal structure within the acinus.

B, Centriacinar emphysema with dilation that initially affects the respiratory bronchioles.

C, Panacinar emphysema with initial distention of the alveolus and alveolar duct.


What is Centriacinar (Centrilobular) Emphysema?

In this type of emphysema the central or proximal parts of the acini , formed by respiratory
bronchioles, are affected, whereas distal alveoli are spared.


both emphysematous and normal airspaces exist within the same acinus and lobule.


The lesions are more common and usually more severe in the upper lobes, particularly in the apical

The walls of the emphysematous spaces often contain large amounts of black pigment.

Inflammation around bronchi and bronchioles is common.

In severe centriacinar
emphysema, the distal acinus may also be involved, and differentiation from panacinar
emphysema becomes difficult.

Centriacinar emphysema occurs predominantly in heavy smokers, often in association with chronic bronchitis.


What is the more common and more severe area affected in centriacinar emphysema?

The lesions are more common and usually more severe in the upper lobes, particularly in the apical


In severe centriacinar
emphysema, the distal acinus may also be involved, and differentiation from panacinar
emphysema becomes difficult. 

T or F




What is Panacinar (Panlobular) Emphysema?

In this type, the acini are uniformly enlarged from the level of the respiratory bronchiole to the
terminal blind alveoli ( Figs. 15-6C and 15-7B ).


The prefix “pan” refers to the entire acinus but
not to the entire lung.

. This type of emphysemais associated with α1-antitrypsin ( α1-
AT) deficiency


What is the difference of centriacinar and panlobular?

In contrast to centriacinar emphysema, panacinar emphysema tends to
occur more commonly in the lower zones and in the anterior margins of the lung, and it is
usually most severe at the bases


What type of emphysema is associated with heavy smoking?



What type of emphysema is associated with  a 1 antitrypsin deficiency?




Q image thumb


A, Centriacinar emphysema. Central areas show marked emphysematous
damage (E), surrounded by relatively spared alveolar spaces.


B, Panacinar emphysema
involving the entire pulmonary lobule.


Where does Panacinar (Panlobular) Emphysema commonly occurs?

panacinar emphysema tends to
occur more commonly in the lower zones and in the anterior margins of the lung, and it is
usually most severe at the bases


cenTrilobular= Top ( most common)

                              Top Gun heavy smoking

panLobular= Low ( most common) 


What is Distal Acinar (Paraseptal) Emphysema?

In this type, the proximal portion of the acinus is normal , and the distal part is predominantly


The emphysema is more striking adjacent to the pleura, along the lobular connective
tissue septa, and at the margins of the lobules.


It occurs adjacent to areas of fibrosis, scarring,
or atelectasis
and is usually more severe in the upper half of the lungs.




What is the characteristic finding of Distal Acinar (Paraseptal) Emphysema?

The characteristic
findings are of multiple, continuous, enlarged airspaces from less than 0.5 cm to more than 2.0
cm in diameter
, sometimes forming cystlike structures.

This type of emphysema probably
underlies many of the cases of spontaneous pneumothorax in young adults.


Where is the most common affected area of  Distal Acinar (Paraseptal) Emphysema?

It occurs adjacent to areas of fibrosis, scarring,
or atelectasis and is usually more severe in the upper half of the lungs


What is Airspace Enlargement with Fibrosis (Irregular Emphysema).?

Irregular emphysema, so named because the acinus is irregularly involved , is almost invariably
associated with scarring

Thus, it may be the most common form of emphysema, because
careful search of most lungs at autopsy shows one or more scars from a healed inflammatory

In most instances, these foci of irregular emphysema are asymptomatic and clinically


What is pathogenesis of the  Airspace Enlargement with Fibrosis (Irregular Emphysema) ?

COPD is characterized by mild chronic inflammation throughout the airways, parenchyma, and
pulmonary vasculature


Macrophages, CD8+ and CD4+ T lymphocytes, and neutrophils are
increased in various parts of the lung.


Activated inflammatory cells release a variety of
, including leukotriene B4, IL-8, TNF, and others, that are capable of damaging lung
structures or sustaining neutrophilic inflammation. [20]


Although details of the genesis of the two
common forms of emphysema—centriacinar and panacinar—remain unsettled, the most
plausible hypothesis to account for the destruction of alveolar walls is the proteaseantiprotease
aided and abetted by imbalance of oxidants and antioxidants


The protease-antiprotease imbalance hypothesis is based on the observation that patients with
a genetic deficiency of the antiprotease α1-antitrypsin have a markedly enhanced tendency to
develop pulmonary emphysema
, which is compounded by smoking ( Fig. 15-8 ).


About 1% of all
patients with emphysema have this defect. α1-antitrypsin
, normally present in serum, tissue
fluids, and macrophages, is a major inhibitor of proteases (particularly elastase) secreted by
neutrophils during inflammation.


α1-antitrypsin is encoded by codominantly expressed genes on
the proteinase inhibitor (Pi) locus on chromosome 14. The Pi locus is extremely polymorphic,
with many different alleles. Most common is the normal (M) allele and the corresponding
phenotype. Approximately 0.012% of the US population is homozygous for the Z allele,
associated with markedly decreased serum levels of α1antitrypsin.

More than 80% of these
individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and with
greater severity if the individual smokes.


What is  α1-antitrypsin

α1-antitrypsin is encoded by codominantly expressed genes on the proteinase inhibitor (Pi) locus on chromosome 14.

The Pi locus is extremely polymorphic,
with many different alleles.


α1-antitrypsin, normally present in serum, tissue
fluids, and macrophages
, is a major inhibitor of proteases (particularly elastase) secreted by
neutrophils during inflammation


More than 80% of these
individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and with
greater severity if the individual smokes. The following sequence is postulated:

  • 1. Neutrophils (the principal source of cellular proteases) are normally sequestered in

peripheral capillaries, including those in the lung, and a few gain access to the alveolar

  • 2. Any stimulus that increases either the number of leukocytes (neutrophils and

macrophages) in the lung or the release of their protease-containing granules
increases proteolytic activity.

  • 3. With low levels of serum α1-antitrypsin, elastic tissue destruction is unchecked and

emphysema results


Q image thumb

FIGURE 15-8 Pathogenesis of emphysema.

Excessive protease activity and reactive oxygen
species are additive in their effects and contribute to tissue damage.

α1-antitrypsin (α1-AT)
deficiency can be either congenital or “functional” as a result of oxidative inactivation

text for details. IL-8, interleukin 8; LTB4, leukotriene B4; TNF, tumor necrosis factor.


Thus, emphysema is seen to result from the destructive effect of high protease activity in
subjects with low antiprotease activity.


The protease-antiprotease imbalance hypothesis also
helps explain the effect of cigarette smoking in the development of emphysema, particularly the
centriacinar form in subjects with normal amounts of α1-antitrypsin:

  • In smokers, neutrophils and macrophages accumulate in alveoli . The mechanism of inflammation is not entirely clear, but possibly involves the direct chemoattractant effects of nicotine as well as the effects of reactive oxygen species contained in smoke. These activate the transcription factor NF-κB, which switches on genes that encode TNF and chemokines, including IL-8. These, in turn, attract and activate neutrophils
  • Accumulated neutrophils are activated and release their granules, rich in a variety of cellular proteases (neutrophil elastase, proteinase 3, and cathepsin G), resulting in tissue damage.
  • Smoking also enhances elastase activity in macrophages; macrophage elastase is not
    inhibited by α1-antitrypsin) and, indeed, can proteolytically digest this antiprotease. There is increasing evidence that in addition to elastase, matrix metalloproteinases derived from macrophages and neutrophils have a role in tissue destruction.


In addition, smoking has a seminal role in perpetuating the oxidant-antioxidant imbalance in the pathogenesis of emphysema.




Normally, the lung contains a healthy complement of antioxidants (superoxide dismutase, glutathione) that keep oxidative damage to a minimum.


Tobacco smoke
contains abundant reactive oxygen species (free radicals), which deplete these antioxidant
mechanisms, thereby inciting tissue damage ( Chapter 1 ).


Activated neutrophils also add to the
pool of reactive oxygen species in the alveoli.

A secondary consequence of oxidative injury is
inactivation of native antiproteases, resulting in “functional” α1-antitrypsin deficiency even in
patients without enzyme deficiency.


How does emphysema leads to funcitonal ariflow obstruction despite absence of mechanical obstruction?

Since small airways are normally tethered by the elastic recoil of the lung parenchyma, the loss
of elastic tissue
in the walls of alveoli that surround respiratory bronchioles reduces radial
traction and thus causes the respiratory bronchioles to collapse during expiration

This leads to
functional airflow obstruction despite the absence of mechanical obstruction.


Until recently loss of elastic recoil was considered to be the sole mechanism of airflow
obstruction in emphysema. However, careful studies in young smokers who died in accidents
have revealed that inflammation of small airways, defined as bronchioles less than 2 mm in
diameter, occurs early in the evolution of COPD. Several changes are seen:

1. goblet cell metaplasia with mucus plugging of the lumen
2. inflammatory infiltration of the walls with neutrophils, macrophages, B cells (sometimes
forming follicles), CD4 and CD8+ T cells
3. thickening of the bronchiolar wall due to smooth muscle hypertrophy and peribronchial



Together these changes narrow the bronchiolar lumen and contribute to airway


One of the perplexing features of COPD is that smoldering inflammation and slow progressive
destruction of the lung parenchyma
often continue for decades after cessation of smoking. [22]

While there are no clear answers, there is emerging evidence that the initial insult in the form of
tobacco smoke
, or other irritants, triggers a maladaptive, self-perpetuating immune response in
which both innate and adaptive components play a role.


Fingers are pointing to pathogenic
CD4+TH17 cells similar to those that are involved in other immunemediated inflammatory
diseases such as Crohn disease, but much remains to be known.


What is the morphology of emphysema?

Advanced emphysema produces voluminous lungs, often overlapping the
and hiding it when the anterior chest wall is removed.


Generally, the upper two thirds of
the lungs are more severely affected

Large apical blebs or bullae are more characteristic of
irregular emphysema secondary to scarring and of distal acinar emphysema. Large alveoli
can easily be seen on the cut surface of formalin-inflated fixed lung



What is the more characteristic of irregular emphysema?

Large apical blebs or bullae are more characteristic of
irregular emphysema secondary to scarring and of distal acinar emphysema


What is the appearance of emphysema microscopically ?

Microscopically, there are abnormally large alveoli separated by thin septa with only focal
centriacinar fibrosis

There is loss of attachments of the alveoli to the outer wall of small

The pores of Kohn are so large that septa appear to be floating or protrude blindly into alveolar spaces with a club-shaped end.

As alveolar walls are destroyed, there is
decrease in the capillary bed.


With advanced disease, there are even larger abnormal
airspaces and possibly blebs or bullae, which often deform and compress the respiratory
bronchioles and vasculature of the lung

Inflammatory changes in small airways were
described earlier.



The clinical manifestations of emphysema do not appear until at least ________

one third of the
functioning pulmonary parenchyma is damaged


What is the Clinical Course of emphysema?

  • Dyspnea is usually the first symptom; it begins insidiously but is steadily progressive.
  • In some patients, cough or wheezing is the chief complaint, easily confused with asthma.
  • Cough and expectoration are extremely variable and depend on the extent of the associated bronchitis.
  • Weight loss is common and can be so severe as to suggest a hidden malignant tumor.
  • Classically, the patient is barrel-chested and dyspneic, with obviously prolonged expiration, sits forward in a hunched-over position, and breathes through pursed lips.



What is the first symptom in emphysema?

Dyspnea is usually the first symptom; it begins
insidiously but is steadily progressive


In some patient what is the chief complaint of emphysema?

In some patients, cough or wheezing is the chief
complaint, easily confused with asthma.


Expiratory airflow limitation, best measured through spirometry, is the key to diagnosis.


In individuals with severe emphysema, cough is often slight, overdistention is severe, diffusion
capacity is low, and blood gas values are relatively normal at rest.

Such patients may
overventilate and remain well oxygenated, and therefore are somewhat ingloriously designated
pink puffers (see Table 15-4 ).

Development of cor pulmonale and eventually congestive heart failure, related to secondary pulmonary vascular hypertension, is associated with a poor prognosis.


Death in most patients with emphysema is due to :

  • (1) respiratory acidosis and coma,
  • (2) right-sided heart failure, and
  • (3) massive collapse of the lungs secondary to pneumothorax.



Treatment options of emphysema include 

  • bronchodilators
  • , steroids,
  • bullectomy,
  • and, in selected patients, lung volume reduction surgery and lung transplantation.
  • Substitution therapy with α1-AT is being evaluated.


TABLE 15-4 -- Emphysema and Chronic Bronchitis

Predominant Bronchitis---- Predominant Emphysema


Age (yr): 40–45                           50–75

Dyspnea: Mild; late                     Severe; early

Cough: Early; copious sputum   Late; scanty sputum

Infections: Common                    Occasional

Respiratory insufficiency: Repeated     Terminal

Cor pulmonale: Common                      Rare; terminal

Airway resistance: Increased               Normal or slightly increased

Elastic recoil: Normal                              Low

Chest xray:: Prominent vessels; large heart Hyperinflation; small heart

Appearance: Blue bloater                     Pink puffer




Other Forms of Emphysema.


Now we come to some conditions in which the term emphysema is applied less stringently and
to some closely related conditions.

  • Compensatory Hyperinflation (Emphysema).
  • Obstructive Overinflation.
  • Bullous Emphysema.


What is Compensatory Hyperinflation (Emphysema)?

This term is sometimes used to designate dilation of alveoli but not destruction of septal walls in
response to loss of lung substance elsewhere.

It is best exemplified by the hyperexpansion of the residual lung parenchyma that follows surgical removal of a diseased lung or lobe.


What is Obstructive Overinflation?

In this condition the lung expands because air is trapped within it .


A common cause is subtotal
obstruction by a tumor or foreign object


Another example is congenital lobar overinflation in
infants, probably resulting from hypoplasia of bronchial cartilage and sometimes associated with
other congenital cardiac and lung abnormalities.



​Overinflation in obstructive lesions occurs

  • (1) because of a ball-valve action of the obstructive agent, so that air enters on inspiration but cannot leave on expiration, or
  • (2) because the bronchus may be totally

obstructed but ventilation through collaterals may bring in air from behind the obstruction.

These collaterals are the pores of Kohn and other direct accessory bronchioloalveolar
connections (the canals of Lambert).




Why is obstructive overinflation can be life threatening emergency?

Obstructive overinflation can be a life-threatening
emergency, because the affected portion distends sufficiently to compress the remaining
normal lung.


What is Bullous Emphysema?

Bullous Emphysema.


This is a descriptive term for large subpleural blebs or bullae (spaces more than 1 cm in
diameter in the distended state) that can occur in any form of emphysema ( Fig. 15-9 ).

represent localized accentuations of emphysema and occur near the apex, sometimes in
relation to old tuberculous scarring.

On occasion, rupture of the bullae may give rise to


Q image thumb

FIGURE 15-9 Bullous emphysema with large subpleural bullae (upper left) .


What is interstitial emphysema?

The entrance of air into the connective tissue stroma of the lung, mediastinum, or
subcutaneous tissue is
called interstitial emphysema.


In most instances, alveolar tears in
pulmonary emphysema provide the avenue of entrance of air
into the stroma of the lung, but
rarely, a wound of the chest that allows air to be sucked in or a fractured rib that punctures the
lung substance may underlie this disorder.


Alveolar tears usually occur when there is a
combination of coughing plus some bronchiolar obstruction
, producing sharply increased
pressures within the alveolar sacs.


Children with whooping cough and bronchitis, patients with
obstruction to the airways (by blood clots, tissue, or foreign bodies) or who are being artificially
ventilated, and individuals who suddenly inhale irritant gases are at risk.



Chronic bronchitis is defined clinically as persistent cough with sputum production for at least 3
months in at least 2 consecutive year
s, in the absence of any other identifiable cause.


bronchitis, so common among habitual smokers and inhabitants of smog-laden cities, is not
nearly as trivial as was once thought.


When Chronic bronchitis persistent for years, it may result to three:

  • (1) progress to COPD,
  • (2) lead to cor pulmonale and heart failure, or
  • (3) cause atypical metaplasia and dysplasia of the respiratory epithelium, providing a rich soil for cancerous transformation.


What is the primiry intitiating factor in chronic bronchitis?

The primary or initiating factor in the genesis of chronic bronchitis seems to be long-standing
irritation by inhaled substances such as tobacco smoke (90% of patients are smokers)
, and
dust from grain, cotton, and silica.


What is the pathogenesis of Chronic bronchitis?

The earliest feature of chronic bronchitis is hypersecretion of
mucus in the large airways,
associated with hypertrophy of the submucosal glands in the
trachea and bronchi. [24]

Proteases released from neutrophils, such as neutrophil elastase and
cathepsin, and matrix metalloproteinases, stimulate this mucus hypersecretion.



As chronic
bronchitis persists, there is also a marked increase in ___________

goblet cells of small airways—small
bronchi and bronchioles—leading to excessive mucus production that contributes to airway



It is thought that both the submucosal gland hypertrophy and the increase in goblet
cells are protective metaplastic reactions against tobacco smoke or other pollutants (e.g., sulfur
dioxide and nitrogen dioxide) 


 T or F?



Although mucus hypersecretion in large airways is the cause of sputum overproduction, it is
now thought that __________can result in physiologically important and early
manifestations of chronic airway obstruction. [
25,] [26]


This feature is similar to that describedearlier in emphysema and seems to be a common denominator in COPD.

accompanying alterations in the small airways of the lung (small bronchi and
bronchioles, less than 2 to 3 mm in diameter) 


What is the role of infection in chronic bronchitis?

The role of infection seems to be secondary.


It is not responsible for the initiation of chronic
but is probably significant in maintaining it and may be critical in producing acute


Cigarette smoke predisposes to infection in more than one way.

It interferes with
ciliary action of the respiratory epithelium, it may cause direct damage to airway epithelium, and
it inhibits the ability of bronchial and alveolar leukocytes to clear bacteria. Viral infections can
also cause exacerbations of chronic bronchitis.


What is the morphology of Chronic bronchitis?

Grossly, there is hyperemia, swelling, and edema of the mucous membranes,
frequently accompanied by excessive mucinous or mucopurulent secretions.

heavy casts of secretions and pus fill the bronchi and bronchioles.

The characteristic
histologic features are chronic inflammation
of the airways (predominantly lymphocytes) and
enlargement of the mucus-secreting glands of the trachea and bronchi.

Although the
numbers of goblet cells increase slightly, the major change is in the size of the mucous
gland (hyperplasia).


The bronchial epithelium may exhibit
squamous metaplasia and dysplasia.

There is marked narrowing of bronchioles caused by
mucus plugging, inflammation, and fibrosis.

In the most severe cases, there may be
obliteration of lumen due to fibrosis (bronchiolitis obliterans).


What is Reid index?

This increase in  the size of the mucous
gland (hyperplasia) can be assessed by the ratio of the thickness of the
mucous gland layer to the thickness of the wall between the epithelium and the cartilage
(Reid index).

The Reid index (normally 0.4) is increased in chronic bronchitis, usually in
proportion to the severity and duration of the disease


What is bronchiolitis obliterans?

obliteration of lumen due to fibrosis (bronchiolitis obliterans).


What is the cardinal symptom of chronic bronchitis?

The cardinal symptom of chronic bronchitis is a persistent cough productive of sputum


What are the clinical features of Chronic bronchitis?

The cardinal symptom of chronic bronchitis is a persistent cough productive of sputum.


For many years no other respiratory functional impairment is present, but eventually dyspnea on
exertion develops.


With the passage of time, and usually with continued smoking, other
elements of COPD may appear, including hypercapnia, hypoxemia, and mild cyanosis (“blue

Differentiation of pure chronic bronchitis from that associated with emphysema can
be made in the classic case (see Table 15-4 ), but, as has been mentioned, many patients with COPD have both conditions. Longstanding severe chronic bronchitis commonly leads to cor
pulmonale with cardiac failure. Death may also result from further impairment of respiratory
function due to superimposed acute infections.


What is asthma?

Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of
wheezing, breathlessness, chest tightness, and cough, particularly at night and/or in the early


These symptoms are usually associated with widespread but variable
bronchoconstriction and airflow limitation that is at least partly reversible, either spontaneously
or with treatment.



What are the hallmarks of asthma?

The hallmarks of the disease are:


  • increased airway responsiveness to a variety of stimuli, resulting in episodic bronchoconstriction;
  • inflammation of the bronchial walls;
  • and increased mucus secretion.


Some of the stimuli that trigger attacks in patients would have little or no effect in subjects with normal airways.

Many cells play a role in the inflammatory
response, in particular lymphocytes, eosinophils, mast cells, macrophages, neutrophils, and
epithelial cells.


What is status asthmaticus?

Individuals with asthma experience attacks of varying severity of dyspnea, coughing, and
wheezing due to sudden episodes of bronchospasm.


Rarely, a state of unremitting attacks,
called status asthmaticus, proves fatal; usually, such patients have had a long history of


Between the attacks, patients may be virtually asymptomatic. There has been a
significant increase in the incidence of asthma in the Western world in the past four decades.


Asthma is categorize into:

  1. Atopic Asthma.
  2. non-atopic


What is atopic asthma?

atopic (evidence of allergen sensitization, often in a patient with a history of allergic rhinitis, eczema)


What is non atopic asthma?

non-atopic (without evidence of allergen


In either type of athma, episodes of bronchospasm can be triggered by diverse
mechanisms, such as respiratory infections (especially viral infections), environmental exposure
to irritants (e.g., smoke, fumes), cold air, stress, and exercise


T or F



Recent studies have suggested
that the recognition of subphenotypes of asthma based on the pattern of airway inflammation
may also be useful.


There is emerging evidence for differing patterns of airway inflammation:

  • eosinophilic,
  • neutrophilic,
  • mixed inflammatory,
  • and pauci-granulocytic asthma

 These subgroups may differ in their etiology, immunopathology, and response to treatment. [28] Asthma may also be classified according to the agents or events that trigger bronchoconstriction.


These include
seasonal, exercise-induced, drug-induced (e.g., aspirin), and occupational asthma, and asthmatic bronchitis in smokers


What is the most common type of asthma?

Atopic asthma.


What is atopic asthma specifically?

This most common type of asthma is a classic example of type I IgE-mediated hypersensitivity
reaction, discussed in detail in Chapter 6 .


The disease usually begins in childhood and is
triggered by environmental allergens, such as dusts, pollens, roach or animal dander, and


A positive family history of asthma is common, and a skin test with the offending antigen
in these patients results in an immediate wheal-and-flare reaction.




How else can you diagnose atopic asthma?

Atopic asthma may also be
diagnosed based on evidence of allergen sensitization by serum radioallergosorbent tests
(called RAST), which identify the presence of IgE specific for a panel of allergens.


What is non atopic asthma specifically?

The second group of individuals with asthma does not have evidence of allergen sensitization,
and skin test results are usually negative.


A positive family history of asthma is less common in
these patients.


Respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) are
common triggers in non-atopic asthma.


In these patients hyperirritability of the bronchial
tree probably underlies their asthma

It is thought that virus-induced inflammation of the
respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants

air pollutants, such as sulfur dioxide, ozone, and nitrogen dioxide, may also contribute
to the
chronic airway inflammation and hyperreactivity that are present in some cases.


What are the common triggers in non-atopic asthma?

Respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) are
common triggers in non-atopic asthma. [29]



Describe Drug-Induced Asthma.

Several pharmacologic agents provoke asthma.


  • Aspirin-sensitive asthma is an uncommon yet

fascinating type, occurring in individuals with recurrent rhinitis and nasal polyps.  These individuals are exquisitely sensitive to small doses of aspirin as well as other nonsteroidal antiinflammatory medications, and they experience not only asthmatic attacks but also urticaria.


It is
probable that aspirin triggers asthma in these patients by inhibiting the cyclooxygenase
pathway of arachidonic acid metabolism without affecting the lipoxygenase route
, thus tipping
the balance toward elaboration of the bronchoconstrictor leukotrienes


What is occupational asthma?

This form of asthma is stimulated by fumes (epoxy resins, plastics), organic and chemical dusts
(wood, cotton, platinum), gases (toluene), and other chemicals (formaldehyde, penicillin


Minute quantities of chemicals are required to induce the attack, which usually
occurs after repeated exposure.


The underlying mechanisms vary according to stimulus and include type I reactions, direct liberation of bronchoconstrictor substances, and hypersensitivity
responses of unknown origin.


What are the major etiologic factors in atopic asthma?

The major etiologic factors in atopic asthma are a genetic predisposition to type I
hypersensitivity (“atopy”) and exposure to environmental triggers that remain poorly


It is postulated that inheritance of susceptibility genes makes individuals prone to
develop strong TH2 reactions
against environmental antigens (allergens) that are ignored or
elicit harmless responses in most individuals.


So what is the pathogenesis after this?

  • In the airways the scene for the reaction is set by

initial sensitization to inhaled allergens, which stimulate induction of TH2 cells ( Fig. 15-10 )

  • TH2 cells secrete cytokines that promote allergic inflammation and stimulate B cells to produce IgE and other antibodies. These cytokines include IL-4, which stimulates the production of IgE; IL-5, which activates locally recruited eosinophils; and IL-13, which stimulates mucus secretion from bronchial submucosal glands and also promotes IgE production by B cells.
  • As in other allergic reactions ( Chapter 6 ), IgE coats submucosal mast cells, and repeat exposure to the allergen triggers the mast cells to release granule contents and produce cytokines and other mediators, which collectively induce the early-phase (immediate hypersensitivity) reaction and the late-phase reaction.


What happens in the early reaciton of asthma and it dominated by what?

The early reaction is dominated by:

  • bronchoconstriction,
  • increased mucus production,
  • and variable degrees of vasodilation with increased vascular permeability.
  • Bronchoconstriction is triggered by direct stimulation of subepithelial vagal (parasympathetic) receptors through both central and local reflexes (including those mediated by unmyelinated sensory C fibers).


What happens in the late phase of asthma?

The late-phase reaction consists largely of inflammation with recruitment of leukocytes, notably
eosinophils, neutrophils, and more T cells.

Leukocyte recruitment is stimulated by chemokines
produced by mast cells, epithelial cells and T cells
, and by other cytokines ( Chapter 2 ).

Epithelial cells are known to produce a large variety of cytokines in response to infectious
agents, drugs, and gases as well as to inflammatory mediators. [31]

This second wave of
mediators stimulates the late reaction

For example, eotaxin, produced by airway epithelial cells, is a potent chemoattractant and activator of eosinophils. [32]

The major basic protein of
eosinophils, in turn, causes epithelial damage [31] and more airway constriction. [33]

mediators have been implicated in the asthmatic response, but the relative importance of each
putative mediator in actual human asthma has been difficult to establish.

The long list of
“suspects” in acute asthma can be subclassified by the clinical efficacy of pharmacologic
intervention with inhibitors or antagonists of the mediators.


The long list of
“suspects” in acute asthma can be subclassified by the clinical efficacy of pharmacologic
intervention with inhibitors or antagonists of the mediators.

  • The first (disappointingly small) group includes putative mediators whose role in
    is clearly supported by efficacy of pharmacologic intervention:
    • (1) leukotrienes C4, D4, and E4, extremely potent mediators that cause prolonged
      as well as increased vascular permeability and increased mucus
      secretion, and 
    • (2) acetylcholine, released from intrapulmonary motor nerves, which can cause airway smooth muscle constriction by directly stimulating muscarinic receptors.
  • A second group includes agents present at the scene of the crime and with potent
    asthma-like effects but whose actual role in acute allergic asthma seems relatively minor
    on the basis of lack of efficacy of potent antagonists or synthesis inhibitors:
    • (1) histamine, a potent bronchoconstrictor;
    • (2) prostaglandin D2, which elicits
      bronchoconstriction and vasodilatation; and (3) platelet-activating factor , which causes
      aggregation of platelets and release of histamine and serotonin from their granules.
      These mediators might yet prove important in other types of chronic or nonallergic
  • Finally, a large third group comprises the suspects for whom specific antagonists or
    inhibitors are not available or have been insufficiently studied as yet
    . These include
    numerous cytokines, such as IL-1, TNF, and IL-6 (some of which exist in a preformed
    state within the mast cell granules), [34] chemokines (e.g., eotaxin), neuropeptides,
    nitric oxide, bradykinin, and endothelins


What is airway remodelling?

Over time, repeated bouts of allergen exposure and immune reactions result in structural
changes in the bronchial wall,
referred to as “airway remodeling.”


These changes, described
later in greater detail, include hypertrophy and hyperplasia of bronchial smooth muscle,
epithelial injury, increased airway vascularity, increased subepithelial mucus gland
hypertrophy/hyperplasia, and deposition of subepithelial collagen.

The complex interactions
between the immune system, airway epithelium, and mesenchymal tissues in the airways are
poorly understood.

Infections with common respiratory pathogens, such as respiratory syncytial
virus and influenza, can exacerbate the chronic changes and cause serious worsening of the
clinical manifestations of the disease.


Although infections are often triggers for asthma, paradoxically, some infections may be


Epidemiologic studies first suggested that the incidence of asthma was greater in
populations not exposed to microbe
s than in those living in an environment with abundant
microbes, and this relationship may explain the increasing incidence of asthma in developed
countries. [35]

These findings have led to the “hygiene hypothesis,” which states that
eradication of infections may promote allergic and other harmful immune responses. Despite a fascination with this idea, there is no plausible explanation for the inverse relationship between
infections and asthma.


Asthma is a complex genetic trait in which multiple susceptibility genes interact with
environmental factors to initiate the pathologic reaction.


As in other complex traits ( Chapter 5 ),
there is considerable variability in the expression of these genes and in the combinations of
polymorphisms present in individual patients, and even in the significance and reproducibility of
reported polymorphisms.


Of the more than 100 genes that have been reported to be
associated with the disease, relatively few have been replicated in multiple patient populations.
Many of these affect the immune response or tissue remodeling.

Some genes may influence the
development of asthma, while others modify asthma severity or the patient's response to
therapy. [36] A few of these are discussed below:

  • chromosome 5q
    • IL-3, IL-4, IL-5, IL-9, and IL-13 and the IL-4
    • receptor for LPS (CD14)
    • IL13 gene
    • CD14
    • TT genotype of CD14
  • class II HLA alleles.
  • ADAM-33
  • β2-adrenergic receptor gene
  • IL-4 receptor gene
  • Mammalian chitinase family


One of the most replicated susceptibility loci for asthma is on chromosome 5q, near the
gene cluster encoding the cytokines________

 IL-3, IL-4, IL-5, IL-9, and IL-13 and the IL-4


The receptor for LPS (CD14), and another candidate gene, the β2-adrenergic
, also map here.


Why is chromosome 5q is of great interest in asthma?

This region is of great interest because of the connection between several of the genes located here and the mechanisms of IgE regulation and
mast cell and eosinophil growth and differentiation.


Among the genes in this cluster,
polymorphisms in the IL13 gene have the strongest and most consistent associations
with asthma or allergic disease.


Among the genes in this cluster in chromosome 5q​
polymorphisms in the ___________ gene have the strongest and most consistent associations
with asthma or allergic disease.



The association between asthma and other forms of atopy with a polymorphism in the
gene encoding the monocyte receptor for endotoxin, CD14, is worthy of additional
comments since it is paradigmatic for studies of gene-environment interactions.


In some
studies, the TT genotype of CD14 has been associated with ____________


Other studies have revealed the opposite, i.e., an
increased risk for atopy.


Further analysis has revealed that the TT genotype is
protective against asthma or allergic sensitization in individuals exposed to low
(household) endotoxin levels, whereas the same genotype is associated with an
increased risk for asthma or allergic sensitization in individuals exposed to high
endotoxin levels (as may occur in those living on farms).

These differences may relate
to the influence of endotoxin levels on the regulation of TH1 vs. TH2 responses.

individuals with the TT genotype high endotoxin levels skew the response towards TH2
type, thus favoring more brisk IgE production and a predisposition to allergy.


studies indicate that the relationship between genotype and phenotype is context
dependent, and help explain some of the discrepant results of association studies in
different populations.

reduced levels of IgE and
reduced risk for asthma and atopy


The tendency to produce IgE antibodies against some but not all antigens, such as
ragweed pollen, may be linked to particular ________

class II HLA alleles.


How does the gene ADAM-33 contribute to asthma?

ADAM-33: ADAM-33 belongs to a subfamily of metalloproteinases related to the MMPs
such as collagenases ( Chapter 3 ).


Although the precise function of ADAM-33 remains
to be elucidated, it is known to be expressed by lung fibroblasts and bronchial smooth
muscle cells.


It is speculated that ADAM-33 polymorphisms accelerate proliferation of
bronchial smooth muscle cells and fibroblasts, thus contributing to bronchial
hyperreactivity and subepithelial fibrosis. [39] ADAM-33 is also associated with decline in
lung functions.


β2-adrenergic receptor gene:



This also maps to 5q and variations in this gene are
associated with differential in vivo airway hyper-responsiveness and in vitro response to
β-agonist stimulation.

Thus, knowledge of the genotype can be of value in predicting
response to treatment.


 Mutliple polymorphic variants in the gene encoding the alpha-chain
of the________ are associated with atopy, elevated total serum IgE, and asthma.

IL-4 receptor gene:


What is chinatase?

Mammalian chitinase family: Chitinases are enzymes that cleave chitin, a polysaccharide
contained in many human parasites and the cell walls of fungi. In humans the chitinase family includes members with and without enzymic activity.

One member with activity,
acidic mammalian chitinase, is up-regulated in and contributes to TH2 inflammation.
Another chitinase family member with no enzymatic activity, YKL-40, is associated with
asthma. Serum levels of YKL-40 correlate with the severity of asthma.


What is the macroscopic finding of status asthmaticus?

In patients dying of status asthmaticus the lungs are overdistended because of
, with small areas of atelectasis.

The most striking macroscopic finding is
occlusion of bronchi and bronchioles by thick, tenacious mucus plugs.




What is the histological appearance of astma 

Histologically, the
mucus plugs contain whorls of shed epithelium, which give rise to the well-known spiral
shaped mucus plugs called Curschmann spirals (these result either from mucus plugging in
subepithelial mucous gland ducts which later become extruded or from plugs in bronchioles).


Numerous eosinophils and Charcot-Leyden crystals are present; the latter are collections
of crystalloid made up of an eosinophil lysophospholipase
binding protein called galectin-


The other characteristic histologic findings of asthma, collectively called “airway


What is Curschmann spirals?

these are shaped mucus plugs which contains  contain whorls of shed epithelium,


What are Charcot-Leyden crystals? 

are collections
of crystalloid made up of an eosinophil lysophospholipase binding protein called galectin-


The other characteristic histologic findings of asthma, collectively called “airway
( Fig. 15-10B ), include:

  • Overall thickening of airway wall
  • Sub-basement membrane fibrosis (due to deposition of type I and III collagen beneath the classic basement membrane composed of type IV collagen and laminin) ( Fig. 15- 11 )
  • • Increased vascularity
  • • An increase in size of the submucosal glands and mucous metaplasia of airway epithelial cells
  • Hypertrophy and/or hyperplasia of the bronchial wall muscle (this has led to the novel therapy of bronchial thermoplasty in which radiofrequency current is applied to the walls of the central airways through a bronchoscopically placed probe, which reduces airway hyper-responsiveness for up to at least a year


Q image thumb

FIGURE 15-11 Bronchial biopsy specimen from an asthmatic patient showing subbasement
membrane fibrosis, eosinophilic inflammation, and muscle hyperplasia.


What is the clinical course of asthma?

Clinical Course.


The classic acute asthmatic attack lasts up to several hours.

In some patients these symptoms
of chest tightness, dyspnea, wheezing, and cough with or without sputum production, persist at
a low level constantly.


In its most severe form, status asthmaticus, the severe acute paroxysm persists for days and even weeks, and under these circumstances airflow obstruction might be
so extreme as to cause severe cyanosis and even death. The clinical diagnosis is aided by the
demonstration of an increase in airflow obstruction (from baseline levels), difficulty with
exhalation (prolonged expiration, wheeze), and elevated eosinophil count in the peripheral
blood and the finding of eosinophils, Curschmann spirals, and Charcot-Leyden crystals in the
sputum (particularly in patients with atopic asthma).


In the usual case, with intervals of freedom
from respiratory difficulty, the disease is more discouraging and disabling than lethal, being
more of a problem in adult women than men. With appropriate therapy to relieve the attacks,
most individuals with asthma are able to maintain a productive life.

Up to 50% of childhood
asthma remits in adolescence only to return in adulthood in a significant number of patients.

other cases there is a variable decline in baseline lung function.


What it Bronchiectasis?

Bronchiectasis is a disease characterized by permanent dilation of bronchi and bronchioles
caused by destruction of the muscle and elastic tissue, resulting from or associated with
chronic necrotizing infections.



To be considered bronchiectasis the dilation must be 

permanent reversible bronchial dilation often accompanies viral and bacterial pneumonia. 

Because of
better control of lung infections, bronchiectasis is now an uncommon condition


develops in association with a variety of conditions, which include the following [44,] [45] :

  • Congenital or hereditary conditions, including cystic fibrosis, intralobar sequestration of the lung, immunodeficiency states, [46] and primary ciliary dyskinesia and Kartagener syndromes
  • Postinfectious conditions, including necrotizing pneumonia caused by bacteria (Mycobacterium tuberculosis, Staphylococcus aureus, Haemophilus influenzae, Pseudomonas), viruses (adenovirus, influenza virus, human immunodeficiency virus [HIV]), and fungi (Aspergillus species)
  • • Bronchial obstruction, due to tumor, foreign bodies, and occasionally mucus impaction, in which the bronchiectasis is localized to the obstructed lung segment
  • • Other conditions, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and post-transplantation (chronic lung rejection, and chronic graft-versus-host disease after bone marrow transplantation)


What are the major conditions associated with bronchiectasis?

Obstruction and infection are the major conditions associated with bronchiectasis, and it is likely
that both are necessary for the development of full-fledged lesions, although either may come

After bronchial obstruction, normal clearing mechanisms are impaired, there is pooling of
secretions distal to the obstruction, and there is inflammation of the airway. Conversely, severe
infections of the bronchi lead to inflammation, often with necrosis, fibrosis, and eventually
dilation of airways.


These mechanisms, infection and obstruction, are most readily apparent in the severe form of
bronchiectasis associated with ___________ Chapter 10 ).

cystic fibrosis 


 In cystic fibrosis the primary defect
in ion transport leads to defective mucociliary action, and accumulation of thick viscid secretions
that obstruct the airways.


This leads to a marked susceptibility to bacterial infections, which further damage the airways.


With repeated infections there is widespread damage to airway walls, with destruction of supporting smooth muscle and elastic tissue, fibrosis, and further
dilatation of bronchi.


The smaller bronchioles become progressively obliterated as a result of
fibrosis (bronchiolitis obliterans).


What is  primary ciliary dyskinesia ?

In primary ciliary dyskinesia , an autosomal recessive syndrome with variable penetrance and a
frequency of 1 in 15,000 to 40,000 births, poorly functioning cilia contribute to the retention of
secretions and recurrent infections
that in turn lead to bronchiectasis.


There is an absence or
shortening of the dynein arms
that are responsible for the coordinated bending of the cilia.

Approximately half of the patients with primary ciliary dyskinesia have Kartagener syndrome
(bronchiectasis, sinusitis, and situs inversus or partial lateralizing abnormality). [48]

The lack of
ciliary activity interferes with bacterial clearance, predisposes the sinuses and bronchi to
infection, and affects cell motility during embryogenesis, resulting in the situs inversus.


with this condition tend to be infertile, as a result of sperm dysmotility.


What is Kartagener syndrome?

Kartagener syndrome
(bronchiectasis, sinusitis, and situs inversus or partial lateralizing abnormality).


What is allergic bronchopulmonary aspergillosis?

Allergic bronchopulmonary aspergillosis is a condition that results from a hypersensitivity
reaction to the fungus Aspergillus fumigatus.

It is also an important complication of asthma and
cystic fibrosis. [49]


Characteristics are high serum IgE levels, serum antibodies to Aspergillus,
intense airway inflammation with eosinophils, and the formation of mucus plugs, which play a
primary role in its pathogenesis.


There is evidence that neutrophil-mediated inflammation and a
relative deficiency of anti-inflammatory cytokines such as IL-10 may also play a role. [50]
Clinically, there are periods of exacerbation and remission that may lead to proximal
bronchiectasis and fibrotic lung disease.


What is the histologic morphology of Bronchiectasis?



The histologic findings vary with the activity and chronicity of the disease.


In the full-blown,
active case there is an intense acute and chronic inflammatory exudation within the walls of
the bronchi and bronchioles, associated with desquamation of the lining epithelium and
extensive areas of necrotizing ulceration. There may be pseudostratification of the columnar
cells or squamous metaplasia
of the remaining epithelium.


In some instances the necrosis
completely destroys the bronchial or bronchiolar walls and forms a lung abscess.

Fibrosis of
the bronchial and bronchiolar walls and peribronchiolar fibrosis develop in the more chronic
cases, leading to varying degrees of subtotal or total obliteration of bronchiolar lumens.


Bronchiectasis usually affects the ____________

lower lobes bilaterally, particularly air
passages that are vertical, and is most severe in the more distal bronchi and bronchioles


When tumors or aspiration of foreign bodies lead to bronchiectasis, the involvement may be
sharply localized to a __________. 

single segment of the lung


***The airways are dilated, sometimes up
to four times normal size.


Characteristically, the bronchi and bronchioles are sufficiently bdilated that they can be followed almost to the pleural surfaces.

By contrast, in the normal
lung, the bronchioles cannot be followed by ordinary gross dissection beyond a point 2 to 3
cm from the pleural surfaces.

On the cut surface of the lung, the transected dilated bronchi
appear as cysts filled with mucopurulent secretions


In the usual case of bronchiectasis, a mixed flora can be cultured from the involved bronchi,
including staphylococci, streptococci, pneumococci, enteric organisms, anaerobic and
microaerophilic bacteria, and (particularly in children) Haemophilus influenzae and
Pseudomonas aeruginosa
. [51]

In allergic bronchopulmonary aspergillosis a few fungal
hyphae can be seen on special stains within the muco-inflammatory contents of the
cylindrically dilated segmental bronchi.

In late stages the fungus may infiltrate the bronchial