Chapter 15: Lung: Chronic Diffuse Interstitial (Restrictive) Diseases Flashcards
What is Chronic interstitial disease?
Chronic interstitial diseases are a heterogeneous group of disorders characterized
predominantly by inflammation and fibrosis of the pulmonary connective tissue, principally the
most peripheral and delicate interstitiumin thealveolar walls.
Many of the entities are of
unknown cause and pathogenesis,some have anintra-alveolar as well as an interstitial
component,and there isfrequent overlap in histologic features among the different conditions.
These disorders account for about 15% of noninfectious diseases seen by pulmonary
physicians.
In general, the clinical and pulmonary functional changes of Chronic Diffuse Interstitial (Restrictive) Diseases are:
those of restrictive lung disease
(see the earlier discussion of obstructive versus restrictive pulmonary diseases).
Patients have
dyspnea, tachypnea, end-inspiratory crackles, and eventual cyanosis, without wheezing or
other evidence of airway obstruction.
What is the classic Chronic Diffuse Interstitial (Restrictive) Diseases?
The classic physiologic features are reductions in carbon
monoxide diffusing capacity, lung volume, and compliance.
Why is Chronic Diffuse Interstitial (Restrictive) Diseases called infiltritative?
Chest radiographs show bilateral
infiltrative lesions in the form of small nodules, irregular lines,orground-glass shadows, hence
the term infiltrative.
What are the circumstances in patients with Chronic infitritative ( restrictive) disease?
Eventually, secondary pulmonary hypertension and right-sided heart failure
with cor pulmonale may result.
Although the entities can often be distinguished in the early
stages.
Why is hard to differentitate the advanced forms of Chronic Infiltrative ( Restrictive) Disease?
the advanced forms are hard to differentiate because they result in scarring and gross
destruction of the lung, often referred to as end-stage lung or honeycomb lung
How do you categorized Chronic infiltrative ( restrictive) disease?
Diffuse
restrictive diseases are categorized based on histology and clinical features
TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease
- FIBROSING
- GRANULOMATOUS
- EOSINOPHILIC
- SMOKING RELATED
TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease
FIBROSING
- Usual interstitial pneumonia (idiopathic pulmonary fibrosis)
- Nonspecific interstitial pneumonia
- Cryptogenic organizing pneumonia
- Associated with connective tissue diseases
- Pneumoconiosis
- Drug reactions
- Radiation pneumonitis
TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease
GRANULOMATOUS
- Sarcoidosis
- Hypersensitivity pneumonitis
TABLE 15-5 – Major Categories of Chronic Interstitial Lung Disease
SMOKING RELATED
- Desquamative interstitial pneumonia
- Respiratory bronchiolitis-associated interstitial lung disease
What is Idiopathic Pulmonary Fibrosis?
The term idiopathic pulmonary fibrosis (IPF) refers to a clinicopathologic syndrome with
characteristic radiologic, pathologic, and clinical features.
**In Europe the term cryptogenic
fibrosing alveolitis is more popular
What is the other name of Idiopathic Pulmonary Fibrosis ?
cryptogenic fibrosing alveolitis
The histologic pattern of fibrosis is referred to as __________, which is required for the diagnosis of IPF but can also be seen in
other diseases,notably connective tissue diseases, chronic hypersensitivity pneumonia, and
asbestosis.
usual interstitial pneumonia (UIP)
The International Multidisciplinary Consensus Classification is an excellent
reference for definitions and understanding of idiopathic interstitial pneumonias
What is the pathogenesis of IPF?
The earlier view was that IPF is initiated by an
unidentified insultthatgives rise to chronic inflammation resulting in fibrosis.
The dismal failure
of potent anti-inflammatory therapy in altering the course of the disease did not support this
view.
The current concept is that IPF is caused by “repeated cycles” of epithelial
activation/injury by some unidentified agent.
There is inflammation and induction of TH2 type T
cell response characterized by the presence of eosinophils, mast cells, IL-4 and IL-13 in the
lesions.
But the significance of this inflammatory response is unknown.
Abnormal epithelial
repair at these sites gives rise to exuberant fibroblastic/myofibroblastic proliferation, leading to
the “fibroblastic foci” that are so characteristic of IPF ( Fig. 15-13 ).
The circuits that drive such
aberrant epithelial repair are not fully understood, but all evidence points to TGF-β1 as the
driver of the process.
TGF-β1 is known to be fibrogenic and is released from injured type I
alveolar epithelial cells ( Fig. 15-13 ).
It favors the transformation of fibroblasts into
myofibroblasts and deposition of collagen and other extracellular matrix molecules.
What are fibroblastic foci that are so characteristic of IPF?
Abnormal epithelial
repairat these sites gives rise toexuberant fibroblastic/myofibroblastic proliferation, leading to
the “fibroblastic foci” that are so characteristic of IPF ( Fig. 15-13 ).
In IPF, though the aberrant epithelial repair isnt fully understood, where does all the evidence of pathology point to?
The circuits that drive such
aberrant epithelial repair are not fully understood, but all evidence points to TGF-β1 as the
driver of the process.
What is TGF- B1?
TGF-β1 is known to be fibrogenic and is released from injured type I alveolar epithelial cells ( Fig. 15-13 ).
- *It favors the transformation of fibroblasts** into
- *myofibroblasts and deposition of collagen** and other extracellular matrix molecules.
FIGURE 15-13 Schematic representation of current understanding of the pathogenesis of
idiopathic pulmonary fibrosis.
What are the two molecules regulated by TGF-β1?
- telomerase activity
- caveolin-1
What is the relation of telomerase shortening in IPF?
The concept that there is an intrinsic abnormality of tissue repair in IPF is supported by the
finding that some patients with familial pulmonary fibrosis have mutations that shorten
telomeres.
Recall that telomeres control cell replications (see Chapters 1 and 7 and with
- *shortening of telomeres alveolar epithelial cells undergo rapid senescence and
apoptosis. **[56,] [57]
Interestingly, TGF-β1 negatively regulates telomerase activity , thus
facilitating epithelial cell apoptosis and the cycle of death and repair.
What does caveolin- 1 does?
Another molecule
regulated by TGF-β1 is caveolin-1, the predominant structural protein of caveolae, flaskshaped
invaginations of the plasma membrane present in many terminally differentiated cells.
Caveolin-1 acts as an endogenous inhibitor of pulmonary fibrosis by limiting TGF-β1–induced
production of extracellular matrix and restoring alveolar epithelial repair processes.
Caveolin-1
is decreased in epithelial cells and fibroblasts of IPF patients, and overexpression of caveolin-1
in a mouse model limits fibrosis. [59]
Such down-regulation may be mediated by the ability of TGF-β1 to attenuate the expression of caveolin-1 in fibroblasts.
Thus, it seems that TGF-β1
has its fingerprints on multiple pathways that regulate pulmonary fibrosis.
Therapeutics directed
toward neutralizing TGF-β1, enhancing telomerase activity or delaying telomere shortening, or
augmenting caveolin-1 may lead to novel treatments for IPF in the future.
What is the macroscopic appearance of IPF?
Grossly, the pleural surfaces of the lung are cobblestoned as a result of the
retraction of scars along the interlobular septa.
The cut surface shows fibrosis (firm, rubbery
white areas)of thelung parenchyma with lower-lobe predominanceanda distinctive
distribution in the subpleural regions and along the interlobular septa.
In IPF the predominance of fibrosis is on the______ and with a distinctive distribution where?
The cut surface shows fibrosis (firm, rubbery
white areas) of the lung parenchyma with lower-lobe predominance and a distinctive
distribution in the subpleural regions and along the interlobular septa.
What is the microscopic appearance of IPF?
Microscopically,
the hallmark of UIP is patchy interstitial fibrosis, which varies in intensity ( Fig. 15-14 ) and
age.
What is the contents of the earliest lesion in IPF?
The earliest lesions contain exuberant fibroblastic proliferation (fibroblastic foci).
With
time these areas become more collagenous and less cellular.
Quite typical is the coexistence
of both early and late lesions ( Fig. 15-15 ).
The dense fibrosis causes the destruction of
alveolar architecture and formation of cystic spaces lined by hyperplastic type II pneumocytes
or bronchiolar epithelium (honeycomb fibrosis)
With adequate sampling, these diagnostic
histologic changes(i.e.,areas of dense collagenous fibrosis with relatively normal lung and
fibroblastic foci)can be identified even in advanced IPF.
T or F
True
There is mild to moderate
inflammation within the fibrotic areas, consisting of mostly lymphocytes, and a few plasma
cells, neutrophils, eosinophils, and mast cells.
Foci of squamous metaplasia and smooth
muscle hyperplasia may be present.
Pulmonary arterial hypertensive changes (intimal fibrosis and medial thickening) are often present. In acute exacerbations diffuse alveolar damage is
superimposed on the UIP pattern
FIGURE 15-14 Usual interstitial pneumonia. The fibrosis is more pronounced in the
subpleural region.
FIGURE 15-15 Usual interstitial pneumonia.
Fibroblastic focus with fibers running parallel
to surface and bluish myxoid extracellular matrix. Honeycombing is present on the left.
What is the clinical course of IPF?
IPF begins insidiously, with gradually increasing dyspnea on exertion and dry cough.
Most
patients are 40 to 70 years old at the time of presentation.
Hypoxemia, cyanosis, and clubbing
occur late in the course.
The progression in an individual patient is unpredictable.
Most patients
have a gradual deterioration of their pulmonary status, despite medical treatment (steroids,
cyclophosphamide, or azathioprine).
In some IPF patients, there are acute exacerbations of the
underlying diseasewith arapid downhill clinical course.
The mean survival is 3 years or less.
Lung transplantation is the only definitive therapy currently available.
What is the only definitive treatment for IPF?
Lung transplantation is the only definitive therapy currently available.
What is Nonspecific Interstitial Pneumonia?
The concept of nonspecific interstitial pneumonia (NSIP) emerged when it was realized that
there is a group of patients with diffuse interstitial lung disease of unknown etiology whose lung
biopsies fail to show diagnostic features of any of the other well-characterized interstitial
diseases.
Despite its “nonspecific” name, NSIP has distinct radiologic and histologic features
and is important to recognize, since these patients have a much better prognosis than do those
with UIP
Which has a better prognosis. IUP or NSIP?
Despite its “nonspecific” name, NSIP has distinct radiologic and histologic features
and is important to recognize, since these patients have a much better prognosis than do those
with UIP.
Morphology.
On the basis of its histology,
NSIP is divided into ____________.
- cellular and
- fibrosing patterns
What is the cellular pattern of the NSIP?
The cellular pattern consists primarily of mild to moderate chronic interstitial inflammation, containing lymphocytes and a few plasma cells, in a uniform or patchy
distribution.
What is the fibrosing pattern of the NSIP?
What is the cellular pattern of the NSIP?
The fibrosing pattern consists of diffuse or patchy interstitial fibrosis without the
temporal heterogeneity that is characteristic of UIP.
- **Fibroblastic foci and honeycombing are
absent. ***
However, in some patients both NSIP and UIP patterns can be seen in different areas
of the lung; the prognosis in these is the same as for UIP
Fibroblastic foci and honeycombing are
present in NSIP?
t or F
False
What is the Clinical Course NSIP?
Patients present with dyspnea and cough of several months’ duration.
They are typically
between 46 and 55 years of age.
Those having the NSIP cellular pattern are somewhat younger than those with the fibrosing pattern or UIP.
Patients with the cellular pattern have a better
outcomethan do those with fibrosing pattern and UIP
What is Cryptogenic Organizing Pneumonia?
Cryptogenic organizing pneumonia is synonymous with the popular term bronchiolitis obliterans
organizing pneumonia;however, theformer is now preferred,since it conveys the essential
features of a clinicopathologic syndromeof unknownetiology and avoids confusion with airway
diseases such as bronchiolitis obliterans.
Patients present with cough and dyspnea and have
subpleural or peribronchial patchy areas of airspace consolidation radiographically
What is the histologic appearance of cryptogenic organizing pneumonia?
Histologically, cryptogenic organizing pneumonia is characterized by the presence of polypoid
plugs of loose organizing connective tissue (Masson bodies)within alveolar ducts, alveoli ( Fig.
15-16 ), and often bronchioles.
The connective tissue is all of the same age, and the underlying lung architecture is normal.
There is no interstitial fibrosis or honeycomb lung.
Some patients
recover spontaneously, but most need treatment with oral steroids for 6 months or longer for
complete recovery.
What are Masson Bodies?
presence of polypoid plugs of loose organizing connective tissue (Masson bodies)
FIGURE 15-16 Cryptogenic organizing pneumonia. Some alveolar spaces are filled with
balls of fibroblasts (Masson bodies), while the alveolar walls are relatively normal. A, Low
power; B, high power
It is important to recognize that organizing pneumonia with intra-alveolar fibrosis is also often
seen as a response to infections or inflammatory injury of the lungs. [66]
These include viral
and bacterial pneumonia, inhaled toxins, drugs, connective tissue disease, and graft-versushost
disease in bone marrow transplant recipients.
The prognosis for these patients is the same
as that for the underlying disorder.
What is Pulmonary Involvement in Connective Tissue Diseases?
Many connective tissue diseases, notably systemic lupus erythematosus, rheumatoid arthritis,
progressive systemic sclerosis (scleroderma), dermatomyositis-polymyositis, and mixed
connective tissue disease, can involve the lung to a lesser or greater degree at some time in
their course.
Pulmonary involvement can occur in different patterns; NSIP, UIP (similar to that
seen in IPF), vascular sclerosis, organizing pneumonia, and bronchiolitis are the most common.
Many connective tissue diseases, notably_______________, can involve the lung to a lesser or greater degree at some time in
their course.
- systemic lupus erythematosus,
- rheumatoid arthritis,
- progressive systemic sclerosis (scleroderma),
- dermatomyositis-polymyositis, and
- mixed connective tissue disease
In the pulmonary involvement in Connective tissue diseases, what are the patterns?
Pulmonary involvement can occur in different patterns;
- NSIP, UIP (similar to that seen in IPF),
- vascular sclerosis,
- organizing pneumonia,
- and bronchiolitis
are the most common
Rheumatoid arthritis: pulmonary involvement may occur in 30% to 40% of patients as
- (1) chronic pleuritis, with or without effusion;
- (2) diffuse interstitial pneumonitis and fibrosis;
- (3) intrapulmonary rheumatoid nodules; or
- (4) pulmonary hypertension
What is the more common pattern in Systemic sclerosis?
• Systemic sclerosis (scleroderma): diffuse interstitial fibrosis (NSIP pattern more common
than UIP)
What is the more common pattern in Lupus erythematosus?
• Lupus erythematosus: patchy, transient parenchymal infiltrates, and occasionally severe
lupus pneumonitis
Pulmonary involvement in these diseases is usually associated with a variable prognosis, partly
dependent on the type of pulmonary disease, although it is still better than that of idiopathic
UIP
What is pneumoconiosis?
The term pneumoconiosis was originally coined to describe the non-neoplastic lung reaction to
inhalation of mineral dusts encountered in the workplace.
Now it also includes diseases induced
by organic as well as inorganic particulatesandchemical fumes and vapors.
A simplified
classification is presented in Table 15-6 . Regulations limiting worker exposure have resulted in
a marked decrease in dust-associated diseases.
TABLE 15-6 – Lung Diseases Caused by Air Pollutants
- MINERAL DUSTS
- ORGANIC DUSTS THAT INDUCE HYPERSENSITIVITY PNEUMONITIS
- ORGANIC DUSTS THAT INDUCE ASTHMA
- CHEMICAL FUMES AND VAPORS
TABLE 15-6 – Lung Diseases Caused by Air Pollutants
MINERAL DUSTS
- Coal dust
- Silica
- Asbestos
- Beryllium
- Iron oxide
- Barium sulfate
- Tin oxide
TABLE 15-6 – Lung Diseases Caused by Air Pollutants
ORGANIC DUSTS THAT INDUCE HYPERSENSITIVITY PNEUMONITIS
- Moldy hay
- Bagasse
- Bird droppings
TABLE 15-6 – Lung Diseases Caused by Air Pollutants
ORGANIC DUSTS THAT INDUCE ASTHMA
- Cotton, flax, hemp
- Red cedar dust
TABLE 15-6 – Lung Diseases Caused by Air Pollutants
CHEMICAL FUMES AND VAPORS
- Nitrous oxide,
- sulfur dioxide,
- ammonia,
- benzene,
- insecticides
What are the diseases caused by Coal dust?
- Anthracosis Coal mining (particularly hard coal)
- Macules
- Progressive massive fibrosis
- Caplan syndrome
What are the diseases caused by Silica ?
- Silicosis
- Caplan syndrome
What are the diseases caused by Asbestos ?
- Asbestosis
- Pleural plaques
- Caplan syndrome
- Mesothelioma
- Carcinoma of the lung,
larynx, stomach, colon
What are the Lung Diseases Caused by Beryllium?
- Acute berylliosis
- Beryllium granulomatosis
- Lung carcinoma
What are the Lung Diseases Caused byIron oxide?
Siderosis
Exposure
Welding
What is the lung disease caused by Barium sulfate?
Baritosis
Which is an exposure from mining?
What is the lung disease caused by Tin oxide?
Stannosis
Exposure from Mining
What is the lung disease caused by Moldy hay?
Farmer’s lung
from farming
What is the lung disease caused by Bagasse?
Bagassosis
from Manufacturing wallboard, paper
What is the lung disease caused by Bird droppings?
Bird-breeder’s lung
From Bird handling
What is the lung disease caused by Cotton, flax, hemp?
Byssinosis
What is the lung disease caused by Red cedar dust?
What is the lung disease caused by Nitrous oxide, sulfur dioxide,
ammonia, benzene, insecticides?
- Bronchitis, asthma
- Pulmonary edema
- ARDS
- Mucosal injury
- Fulminant poisoning
From occupational and accidental exposure
Although the pneumoconioses result from well-defined occupational exposure to specific
airborne agents, particulate air pollution also has deleterious effects on the general population,
especially in urban areas. Studies have found increased morbidity (e.g., asthma incidence) and
mortality rates in populations that are exposed to high ambient air particulate levels, [68,] [69]
leading to calls for greater efforts to reduce the levels of particulates in urban air
The development of a pneumoconiosis depends on
(1) the amount of dust retained in the lung
and airways;
(2) the size, shape, and therefore buoyancy of the particles;
(3) particle solubility and physiochemical reactivity; and
(4) the possible additional effects of other irritants (e.g.,
concomitant tobacco smoking).
The amount of dust retained in the lungs is determined by :
the dust concentration in ambient air,
the duration of exposure, and the effectiveness of clearance mechanisms.
Any influence, such
as cigarette smoking, that affects the integrity of the mucociliary apparatus significantly
predisposes to the accumulation of dust.
The most dangerous particles range from _______- in
diameter because they may reach the terminal small airways and air sacs and settle in their
linings.
1 to 5 μm
Under normal conditions there is a small pool of intra-alveolar macrophages, and this is
expanded by recruitment of more macrophages when dust reaches the alveolar spaces.
The
protection provided by phagocytosis of particles, however, can be overwhelmed by a large dust
burden by specific chemical interactions of the particles with cells.
The solubility and cytotoxicity of particles , which are influenced to a considerable extent by
their size, modify the nature of the pulmonary response.
In general, the smaller the particle, the
more likely it is to appear in the pulmonary fluids and reach toxic levels rapidly, depending, of
course, on the solubility of the agent.
T or F
True
Therefore, smaller particles tend to cause acute lung
injury.
Larger particles resist dissolution and so may persist within the lung parenchyma for
years.
These tend to evoke fibrosing collagenous pneumoconioses, such as is characteristic of
silicosis.
Some of the particles may be taken up by epithelial cells or may cross the epithelial
cell lining and interact directly with fibroblasts and interstitial macrophages.
Some may reach
the lymphatics by direct drainage or within migrating macrophages and thereby initiate an
immune response to components of the particulates or to self-proteins modified by the particles
or both. This response amplifies the intensity and the duration of the local reaction.
Although
tobacco smoking worsens the effects of all inhaled mineral dusts, the effects of asbestos are
particularly magnified by smoking. The effects of inhaled particles are not confined to the lung alone, since solutes from particles can enter the blood and lung inflammation invokes systemic
responses
In general, only a small percentage of exposed people develop occupational respiratory
diseases, implying a genetic predisposition to their development. [71]
In one study, genetic
variation of serum and erythrocytic proteins was shown to correlate with susceptibility to
developing silicosis, chronic bronchitis, and occupational asthma. [72]
Many of the diseases
listed in Table 15-6 are quite uncommon. Hence only a selected few that cause fibrosis of the
lung are presented next.