The Lung

Pathogenesis

ALI/ARDS is initiated by injury of pneumocytes and pulmonary endothelium, setting in motion a vicious cycle of increasing inflammation and pulmonary damage ( Fig. 15.3 ).

• Endothelial activation is an important early event. In some instances, endothelial activation is secondary to pneumocyte injury, which is sensed by resident alveolar macrophages. In response, these immune sentinels secrete mediators such as tumor necrosis factor (TNF) that act on the neighboring endothelium. Alternatively, circulating inflammatory mediators may activate pulmonary endothelium directly in the setting of severe tissue injury or sepsis. Some of these mediators injure endothelial cells, while others (notably cytokines) induce endothelial cells to express increased levels of adhesion molecules, procoagulant proteins, and chemokines.

• Adhesion and extravasation of neutrophils. Neutrophils adhere to the activated endothelium and migrate into the interstitium and the alveoli, where they degranulate and release inflammatory mediators including proteases, reactive oxygen species, and cytokines. Experimental evidence suggest that neutrophil extracellular traps (NETs) are released and also contribute directly to lung damage. These injuries and associated proinflammatory factors set in motion a vicious cycle of inflammation and endothelial damage that lies at the heart of ALI/ARDS.

• Accumulation of intra-alveolar fluid and formation of hyaline membranes. Endothelial activation and injury make pulmonary capillaries leaky, allowing interstitial and intra-alveolar edema fluid to form. Damage and necrosis of type II alveolar pneumocytes lead to surfactant abnormalities, further compromising alveolar gas exchange. Ultimately the inspissated protein-rich edema fluid and debris from dead alveolar epithelial cells organize into hyaline membranes, a characteristic feature of ALI/ARDS.

• Resolution of injury is impeded in ALI/ARDS due to epithelial necrosis and inflammatory damage that impairs the ability of remaining cells to assist with edema resorption. Eventually, however, if the inflammatory stimulus lessens, macrophages remove intra-alveolar debris and release fibrogenic cytokines such as transforming growth factor β (TGF-β) and platelet-derived growth factor. These factors stimulate fibroblast growth and collagen deposition, leading to fibrosis of alveolar walls. Residual type II pneumocytes proliferate to replace type I pneumocytes, reconstituting the alveolar lining. Endothelial restoration occurs through proliferation of uninjured capillary endothelium.

The lesions in ARDS are not evenly distributed, and as a result there are typically areas that are stiff and poorly aerated and regions that have nearly normal levels of compliance and ventilation. Because poorly aerated regions continue to be perfused, there is a mismatch of ventilation and perfusion, a phenomenon that exacerbates the hypoxemia and cyanosis.

Epidemiologic studies have shown that ALI/ARDS is more common and has a worse prognosis in chronic alcoholics and in smokers. Genome-wide association studies have identified a number of genetic variants that increase the risk of ARDS, some of which map to genes linked to inflammation and coagulation.

Morphology

In the acute exudative stage, the lungs are heavy, firm, red, and boggy. They exhibit congestion, interstitial and intra-alveolar edema, inflammation, fibrin deposition, and diffuse alveolar damage. The alveolar walls become lined with waxy hyaline membranes ( Fig. 15.4 ) that are morphologically similar to those seen in hyaline membrane disease of neonates ( Chapter 10 ). Alveolar hyaline membranes consist of fibrin-rich edema fluid mixed with the remnants of necrotic epithelial cells. In the proliferative or organizing stage, type II pneumocytes proliferate, and granulation tissue forms in the alveolar walls and spaces. In most cases the granulation tissue resolves, leaving minimal functional impairment. Sometimes, however, fibrotic thickening (scarring) of the alveolar septa ensues (late fibrotic stage).

Clinical Features

Profound dyspnea and tachypnea herald ALI/ARDS, followed by increasing respiratory failure, hypoxemia, cyanosis, and the appearance of diffuse bilateral infiltrates on radiographic examination. Hypoxemia may be refractory to oxygen therapy due to ventilation-perfusion mismatch, and respiratory acidosis can develop. Early in the course, the lungs become stiff due to loss of functional surfactant, leading to the need for intubation and high ventilatory pressures to maintain adequate gas exchange.

There are no proven specific treatments for ARDS, which is common in acutely ill patients and continues to take a high toll, even in patients receiving state-of-the-art supportive care. In a 2016 study of intensive care units in 50 countries, the incidence of ARDS was 10.4%, and mortality rates were 35% for mild, 40% for moderate, and 46% for severe ARDS. The majority of deaths are attributable to sepsis, multiorgan failure, or severe lung injury. Most survivors recover pulmonary function, but in a minority of patients, the lung damage results in interstitial fibrosis and chronic pulmonary disease.

Key Concepts

Acute Respiratory Distress Syndrome

• ARDS is a clinical syndrome of progressive respiratory insufficiency caused by diffuse alveolar damage in the setting of sepsis, severe trauma, or diffuse pulmonary infection.

• Damage to endothelial and alveolar epithelial cells and secondary inflammation are the key initiating events and the basis of lung damage.

• The characteristic histologic finding is hyaline membranes lining alveolar walls, accompanied by edema, scattered neutrophils and macrophages, and epithelial necrosis.

Pathogenesis

Clinically significant emphysema is largely confined to smokers and to patients with α ₁ -antitrypsin deficiency, highlighting the importance of these two etiologic factors. Mechanisms relating to these factors that contribute to the development of emphysema include the following ( Fig. 15.8 ):

• Toxic injury and inflammation. Inhaled cigarette smoke and other noxious particles damage respiratory epithelium and cause inflammation, which results in variable degrees of parenchymal destruction. A wide variety of inflammatory mediators (including leukotriene B ₄ , interleukin [IL]-8, TNF, and others) are increased in the affected parts of the lung. These mediators are released by resident epithelial cells and macrophages and variously attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors). Chronic inflammation also leads to the accumulation of T and B cells in affected parts of the lung, but the role of adaptive immunity in emphysema is currently uncertain.

• Protease-antiprotease imbalance. Several proteases are released from the inflammatory cells and epithelial cells that break down connective tissue components. In patients who develop emphysema, there is a relative deficiency of protective antiproteases, which in some instances has a genetic basis (discussed later).

• Oxidative stress. Substances in tobacco smoke, alveolar damage, and inflammatory cells all produce oxidants, which may beget tissue damage, endothelial dysfunction, and inflammation. The role of oxidants is supported by studies of mice in which the NRF2 gene is inactivated. NRF2 is a transcription factor that serves as a sensor for oxidants in many cell types including alveolar epithelial cells. Intracellular oxidants activate NRF2, which upregulates the expression of genes that protect cells from oxidant damage. Mice without NRF2 are significantly more sensitive to tobacco smoke than normal mice, and genetic variants in NRF2, NRF2 regulators, and NRF2 target genes are all associated with smoking-related lung disease in humans.

• Infection. Although infection is not thought to play an initiating role in the tissue destruction, bacterial and/or viral infections may acutely exacerbate existing disease.

The idea that proteases are important is based in part on the observation that patients with a genetic deficiency of the antiprotease α ₁ -antitrypsin have a markedly enhanced tendency to develop emphysema that is compounded by smoking. About 1% of all patients with emphysema have this defect. α ₁ -Antitrypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases (particularly elastase) secreted by neutrophils during inflammation. It is encoded by the proteinase inhibitor (Pi) locus on chromosome 14. The Pi locus is polymorphic, and approximately 0.012% of the U.S. population is homozygous for the Z allele, a genotype associated with very low serum levels of α ₁ -antitrypsin. More than 80% of ZZ individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and is of greater severity if the individual smokes. It is postulated that any injury (e.g., that induced by smoking) that increases the activation and influx of neutrophils into the lung leads to local release of proteases, which in the absence of α ₁ -antitrypsin activity result in excessive digestion of elastic tissue and, with time, emphysema.

Several other genetic variants have also been linked to risk of emphysema. Among these are variants of the nicotinic acetylcholine receptor that are hypothesized to influence the addictiveness of tobacco smoke and thus the behavior of smokers. Not surprisingly, the same variants are also linked to lung cancer risk, emphasizing the importance of smoking in both of these diseases.

A number of factors contribute to airway obstruction in emphysema. Small airways are normally held open 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, leading to collapse of respiratory bronchioles during expiration and functional airflow obstruction in the absence of mechanical obstruction. In addition, even young smokers often have changes related to small airway inflammation that also contribute to airway narrowing and obstruction (described later).

Morphology

Advanced emphysema produces voluminous lungs, often overlapping the heart anteriorly. Generally, in patients with smoking-related disease, the upper two-thirds of the lungs are more severely affected. Large alveoli can easily be seen on the cut surface of fixed lungs (see Fig. 15.7 ). Apical blebs or bullae characteristic of irregular emphysema may appear in patients with advanced disease.

Microscopically, abnormally large alveoli are separated by thin septa with focal centriacinar fibrosis. There is loss of attachments between alveoli and the outer wall of small airways. 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 a decrease in the capillary bed area. 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 are often superimposed (described next under chronic bronchitis), as are vascular changes related to pulmonary hypertension stemming from local hypoxemia and loss of capillary beds.

Pathogenesis

The primary or initiating factor in the genesis of chronic bronchitis is exposure to noxious or irritating inhaled substances such as tobacco smoke (90% of those affected are smokers) and dust from grain, cotton, and silica. Several factors contribute to its pathogenesis.

• Mucus hypersecretion. The earliest feature of chronic bronchitis is hypersecretion of mucus in the large airways, associated with enlargement of the submucosal glands in the trachea and bronchi. The basis for mucus hypersecretion is incompletely understood, but it appears to involve inflammatory mediators such as histamine and IL-13. With time, there is also a marked increase in goblet cells in small airways—small bronchi and bronchioles—leading to excessive mucus production that contributes to airway obstruction. It is thought that both the enlargement of submucosal glands and the increase in numbers of goblet cells are protective reactions against tobacco smoke or other pollutants (e.g., sulfur dioxide and nitrogen dioxide).

• Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. There is substantial evidence that smoking leads to acquired CFTR dysfunction, which in turn causes the secretion of abnormal, dehydrated mucus that exacerbates the severity of chronic bronchitis.

• Inflammation. Inhalants that induce chronic bronchitis cause cellular damage, eliciting both acute and chronic inflammatory responses involving neutrophils, lymphocytes, and macrophages. Long-standing inflammation and accompanying fibrosis involving small airways (small bronchi and bronchioles, less than 2 to 3 mm in diameter) can also lead to chronic airway obstruction.

• Infection. Infection does not initiate chronic bronchitis, but is probably significant in maintaining it and may be critical in producing acute exacerbations.

Cigarette smoke predisposes to chronic bronchitis in several ways. Not only does it damage airway-lining cells, leading to chronic inflammation, but it also interferes with the ciliary action of the respiratory epithelium, preventing the clearance of mucus and increasing the risk of infection.

Morphology

Grossly, there is hyperemia, swelling, and edema of the mucous membranes, frequently accompanied by excessive mucinous or mucopurulent secretions. Sometimes, heavy casts of secretions and pus fill the bronchi and bronchioles. The characteristic microscopic features are chronic inflammation of the airways (predominantly lymphocytes and macrophages); thickening of the bronchiolar wall due to smooth muscle hypertrophy, deposition of extracellular matrix in the muscle layer, and peribronchial fibrosis; goblet cell hyperplasia; and enlargement of the mucus-secreting glands of the trachea and bronchi. Of these, the most striking change is an increase in the size of the mucous glands. This increase 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. The mucus plugging, inflammation, and fibrosis may lead to marked narrowing of bronchioles, and in the most severe cases, there may be obliteration of lumen due to fibrosis (bronchiolitis obliterans) . The bronchial epithelium may also exhibit squamous metaplasia and dysplasia due to the irritating and mutagenic effects of substances in tobacco smoke.

Clinical Features of COPD

Most affected patients have a smoking history of 40 pack-years or greater. COPD often presents insidiously with slowly increasing dyspnea on exertion and chronic cough with sputum production, slight at first but increasing over time. Other patients present with exacerbations caused by superimposed infection that can lead to confusion with other disorders, such as asthma (due to wheezing). The most important diagnostic test is spirometry, which typically shows an FEV ₁ /FVC ratio of less than 0.7.

Once COPD appears, symptoms often wax and wane over time and are generally worse in the morning. The clinical picture varies according to the severity of the disease and the relative contributions of emphysematous and bronchitic changes ( Table 15.4 ). At one extreme end of the spectrum lie “pink puffers,” patients in whom emphysema dominates. Classically, the patient is barrel-chested and dyspneic, with obviously prolonged expiration, sits forward in a hunched-over position, and breathes through pursed lips. Cough is often slight, overdistention of the lungs is severe, diffusion capacity is low, and blood gas values are relatively normal at rest. Weight loss is common and can be so severe as to suggest an occult cancer. At the other end lie patients with pure chronic bronchitis, ingloriously referred to as “blue bloaters.” Their cardinal symptom is a persistent cough productive of sputum, coupled with hypercapnia, hypoxemia, and mild cyanosis. Most patients are somewhere in the middle, with signs and symptoms stemming from both bronchitic and emphysematous changes.

Treatment options include smoking cessation, oxygen therapy, long-acting bronchodilators with inhaled corticosteroids, antibiotics, physical therapy, bullectomy, and, in selected patients, lung volume reduction surgery and lung transplantation. Even with intervention, however, COPD often progresses and frequently proves fatal. Long-standing COPD, particularly in patients with a bronchitic component, commonly leads to pulmonary hypertension, cor pulmonale, and death due to heart failure. Death may also result from acute respiratory failure due to acute infections superimposed on COPD. In patients with emphysematous changes, subpleural blebs may rupture, leading to fatal pneumothorax. The best hope for a major change in this dire picture is more effective programs aimed at prevention of smoking and other environmental exposures.

Key Concepts

Chronic Obstructive Pulmonary Disease

• Most common in long-standing tobacco smokers (typically >40 pack-years); air pollutants also contribute.

• Underlying pulmonary pathology usually includes both chronic bronchitis and emphysema.

• Often fatal due to development of heart failure or of respiratory failure due to superimposed infection.

Emphysema

• In COPD, usually follows a centroacinar distribution characterized by permanent enlargement of airspaces distal to terminal bronchioles.

• Particularly severe in patients with α ₁ -antitrypsin deficiency, in which a panacinar pattern of emphysematous change may be seen.

• Tissue destruction is caused by elastases and oxidants released from inflammatory cells, particularly neutrophils, which are responding to cellular injury caused by tobacco smoke and pollutants.

Chronic Bronchitis

• Defined as persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.

• Dominant pathologic features are mucus hypersecretion due to enlargement of mucus-secreting glands and chronic inflammation associated with bronchiolar wall fibrosis.

Other Forms of Emphysema

In addition to emphysema occurring in the setting of COPD, several other conditions may be associated with lung overinflation or focal emphysematous change and are mentioned here in brief.

• Compensatory hyperinflation. This term is used to designate dilation of alveoli in response to loss of lung substance elsewhere, for example, following surgical removal of a lung or lobe with cancer.

• Obstructive overinflation. In this condition the lung expands because air is trapped within it. A common cause is subtotal obstruction of an airway by a tumor or foreign object. In infants, it may be caused by congenital lobar overinflation , which most often results from hypoplasia of bronchial cartilage. Overinflation occurs either (1) because of an obstruction that acts as ball valve, allowing air to enter on inspiration while preventing its exodus on expiration, or (2) because collaterals bring in air behind the obstruction. These collaterals consist of the pores of Kohn and other direct accessory bronchioloalveolar connections (the canals of Lambert ). Obstructive overinflation can be life-threatening if the affected portion distends sufficiently to compress the adjacent uninvolved lung.

• Bullous emphysema. This is a descriptive term for large subpleural blebs or bullae (spaces greater than 1 cm in diameter in the distended state) that can occur in any form of emphysema ( Fig. 15.9 ), often near the apex. Rupture of the bullae may give rise to pneumothorax.

  

• Interstitial emphysema. Entrance of air into the connective tissue stroma of the lung, mediastinum, or subcutaneous tissue produces interstitial emphysema. In most instances, it is caused by alveolar tears that occur in patients with pulmonary emphysema due to transient increases in intra-alveolar pressure, for example, during coughing. Less commonly, chest wounds or fractured ribs that puncture the lung provide the portal for entrance of air into surrounding soft tissues.

Pathogenesis

Atopic asthma, the most common form of the disease, is caused by a Th2-mediated IgE response to environmental allergens in genetically predisposed individuals. Airway inflammation is central to the disease pathophysiology and causes airway dysfunction partly through the release of potent inflammatory mediators and partly through remodeling of the airway wall. As the disease becomes more severe, there is increased local secretion of growth factors, which induce mucous gland enlargement, smooth muscle proliferation, angiogenesis, and fibrosis. Varying combinations of these processes help explain the different asthma subtypes, their response to treatment, and their natural history over a person's lifetime.

The contributions of the immune response, genetics, and environment are discussed separately below, although they are closely intertwined.

Th2 Responses, IgE, and Inflammation

A fundamental abnormality in asthma is an exaggerated Th2 response to normally harmless environmental antigens ( Fig. 15.10 ). Th2 cells secrete cytokines that promote 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. The T cells and epithelial cells secrete chemokines that recruit more T cells and eosinophils, thus exacerbating the reaction. As in other allergic reactions ( Chapter 6 ), IgE binds to the Fc receptors on 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.

The early-phase reaction is dominated by bronchoconstriction, increased mucus production, variable degrees of vasodilation, and increased vascular permeability. Bronchoconstriction is triggered by direct stimulation of subepithelial vagal (parasympathetic) receptors through both central and local reflexes triggered by mediators produced by mast cells and other cells in the reaction. The late-phase reaction is dominated by recruitment of leukocytes, notably eosinophils, neutrophils, and more T cells. Although Th2 cells are the dominant T-cell type involved in the disease, other T cells that contribute to the inflammation include Th17 (IL-17 producing) cells, which recruit neutrophils.

Many mediators produced by leukocytes and epithelial cells have been implicated in the asthmatic response. The long list of “suspects” in acute asthma can be ranked based on the clinical efficacy of pharmacologic intervention with antagonists of specific mediators.

• Mediators whose role in bronchospasm is clearly supported by efficacy of pharmacologic intervention are (1) leukotrienes C ₄ , D ₄ , and E ₄ , which cause prolonged bronchoconstriction as well as increased vascular permeability and increased mucus secretion; (2) acetylcholine, released from intrapulmonary parasympathetic nerves, which can cause airway smooth muscle constriction by directly stimulating muscarinic receptors; (3) IL-5, antagonists of which are effective in treating severe forms of asthma that are associated with peripheral blood eosinophilia; and (4) galectin-10 (GAL10), which is released from eosinophils and forms crystals known as Charcot-Leyden crystals . Long recognized as a feature of asthma, recent studies have shown that these crystals are strong inducers of inflammation and mucus production.

• A second group of agents are present at the “scene of the crime” but seem to have relatively minor contributions on the basis of lack of efficacy of potent antagonists or synthesis inhibitors. These include (1) histamine, a potent bronchoconstrictor; (2) prostaglandin D ₂ , which elicits bronchoconstriction and vasodilation; and (3) platelet-activating factor, which causes aggregation of platelets and release of serotonin from their granules. These mediators might yet prove important in certain types of chronic or non-allergic asthma.

• Finally, a large third group comprises “suspects” for whom specific antagonists or inhibitors are not available or have been insufficiently studied as yet. These include IL-4, IL-13, TNF, chemokines (e.g., eotaxin, also known as CCL11), neuropeptides, nitric oxide, bradykinin, and endothelins.

It is thus clear that multiple mediators contribute to the acute asthmatic response. Moreover, the composition of this “mediator soup” likely varies among individuals or different types of asthma. The appreciation of the importance of inflammatory cells and mediators in asthma has led to greater emphasis on anti-inflammatory drugs, such as corticosteroids, in its treatment.

Environmental Factors

Asthma is a disease of industrialized societies where the majority of people live in cities. Two ideas, neither wholly satisfying, have been proposed to explain this association. First, industrialized environments contain many airborne pollutants that can serve as allergens to initiate the Th2 response. Second, city life tends to limit the exposure of very young children to certain antigens, particularly microbial antigens, and exposure to such antigens may protect children from asthma and atopy. The idea that microbial exposure during early life reduces the later incidence of allergic (and some autoimmune) diseases has been popularized as the hygiene hypothesis. Although the underlying mechanisms of this protective effect are unclear, it has spurred trials of probiotics and intentional early exposure of children to putative allergens to decrease their risk of later developing allergies.

Infections do not cause asthma by themselves, but may be important co-factors. Young children with aeroallergen sensitization who develop lower respiratory tract viral infections (rhinovirus type C, respiratory syncytial virus) have a 10- to 30-fold increased risk of developing persistent and/or severe asthma. Both viral and bacterial infections (identified by cultures and non-culture tools) are associated with acute exacerbations of the disease.

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, subepithelial mucous gland enlargement, and subepithelial fibrosis.

A small subset of patients with asthma, many of whom have severe disease that is refractory to glucocorticoids, has inflammatory infiltrates that are enriched for neutrophils rather than eosinophils. This form of the disease may be driven by a Th17 T-cell response to chronic bacterial colonization of the lung.

Morphology

In patients dying of acute severe asthma (status asthmaticus), the lungs are overinflated and contain small areas of atelectasis. The most striking gross finding is occlusion of bronchi and bronchioles by thick, tenacious mucus plugs, which often contain shed epithelium. A characteristic finding in sputum or bronchoalveolar lavage specimens of patients with atopic asthma is Curschmann spirals, which may result from extrusion of mucus plugs from subepithelial mucous gland ducts or bronchioles. Also present are numerous eosinophils and Charcot-Leyden crystals composed of the eosinophil-derived protein galectin-10. The other characteristic histologic findings of asthma, collectively called airway remodeling ( Figs. 15.10B and 15.11 ), include:

• Thickening of airway wall

• Sub–basement membrane fibrosis (due to deposition of type I and III collagens)

• Increased vascularity

• Increase in the size of the submucosal glands and number of airway goblet cells

• Hypertrophy and/or hyperplasia of the bronchial wall muscle with increased extracellular matrix

While acute airflow obstruction is primarily attributed to muscular bronchoconstriction, acute edema, and mucus plugging, airway remodeling may contribute to chronic irreversible airway obstruction.

Clinical Features

A classic acute asthmatic attack lasts up to several hours. In some patients, however, the cardinal symptoms of chest tightness, dyspnea, wheezing, and coughing (with or without sputum production) are present at a low level constantly. In its most severe form, acute severe asthma, the paroxysm persists for days or even weeks, sometimes causing airflow obstruction that is so extreme that marked cyanosis or even death ensues.

The diagnosis is based on demonstration of an increase in airflow obstruction (from baseline levels); difficulty with exhalation (prolonged expiration, wheeze); and (in those with atopic asthma) identification of eosinophilia in the peripheral blood and eosinophils, Curschmann spirals, and Charcot-Leyden crystals in the sputum. In the usual case with intervals of freedom from respiratory difficulty, the disease is more discouraging and disabling than lethal, and most individuals are able to maintain a productive life.

Therapy is based on the severity of the disease. The centerpieces of standard therapy are bronchodilators, glucocorticoids, and leukotriene antagonists. For severe and difficult-to-treat asthma in adolescents and adults, novel biologic therapies targeting inflammatory mediators such as IL-5 blocking antibodies, which is effective in severe asthma associated with Th2 immune responses and peripheral blood eosinophilia, are now available. Up to 50% of childhood asthma remits in adolescence only to return in adulthood in a significant number of patients. In other cases there is a variable decline in baseline lung function over time.

Key Concepts

Asthma

• Asthma is characterized by reversible bronchoconstriction caused by airway hyperresponsiveness to a variety of stimuli.

• Atopic asthma is caused by a Th2 and IgE-mediated immunologic reaction to environmental allergens and is characterized by acute-phase (immediate) and late-phase reactions. The Th2 cytokines IL-4, IL-5, and IL-13 are important mediators.

• Triggers for non-atopic asthma are less clear but include viral infections and inhaled air pollutants, which can also trigger atopic asthma.

• Eosinophils are key inflammatory cells in atopic asthma; other inflammatory cells implicated in its pathogenesis include mast cells, neutrophils, and T lymphocytes.

• Airway remodeling (sub–basement membrane fibrosis, hypertrophy of bronchial glands, and smooth muscle hyperplasia) adds an irreversible component to the obstructive disease.

Pathogenesis

Obstruction and infection are the major conditions associated with bronchiectasis. The infections that lead to bronchiectasis are usually the result of a defect in airway clearance. Sometimes this defect stems from airway obstruction, leading to distal pooling of secretions.

Both mechanisms are readily apparent in a severe form of bronchiectasis that is associated with cystic fibrosis ( Chapter 10 ). In cystic fibrosis the primary defect in ion transport results in thick viscous secretions that perturb mucociliary clearance and lead to airway obstruction. This sets the stage for chronic bacterial infections, which cause widespread damage to airway walls. With destruction of supporting smooth muscle and elastic tissue, the bronchi become markedly dilated, while smaller bronchioles are progressively obliterated as a result of fibrosis (bronchiolitis obliterans).

Primary ciliary dyskinesia is an autosomal recessive disease with a frequency of 1 in 10,000 to 20,000 births. The disease-causing mutations result in ciliary dysfunction due to defects in ciliary motor proteins (e.g., mutations involving dynein), again preventing mucociliary clearance, setting the stage for recurrent infections that lead to bronchiectasis. Ciliary function also is necessary during embryogenesis to ensure proper rotation of the developing organs in the chest and abdomen; in its absence, their location becomes a matter of chance. As a result, approximately half of patients with primary ciliary dyskinesia have Kartagener syndrome, marked by situs inversus or a partial lateralizing abnormality associated with bronchiectasis and sinusitis. Males with this condition also tend to be infertile as a result of sperm dysmotility.

Allergic bronchopulmonary aspergillosis occurs in patients with asthma or cystic fibrosis and frequently leads to the development of bronchiectasis. It is a hyperimmune response to the fungus Aspergillus fumigatus. Sensitization to Aspergillus leads to activation of Th2 helper T cells, which release cytokines that recruit eosinophils and other leukocytes. Characteristically, there are high serum IgE levels, serum antibodies to Aspergillus, intense airway inflammation with eosinophils, and formation of mucus plugs, which play a primary role in the development of bronchiectasis.

Morphology

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 tumor or aspiration of foreign bodies leads to bronchiectasis, the involvement is localized. The airways are dilated, sometimes up to four times normal size. Characteristically, the bronchi and bronchioles are so dilated that they can be followed almost to the pleural surfaces. By contrast, in the normal lung, the bronchioles cannot be followed by eye beyond a point 2 to 3 cm from the pleural surfaces. On the cut surface of the lung, the dilated bronchi appear cystic and are filled with mucopurulent secretions ( Fig. 15.12 ).

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 ulceration. There also may be squamous metaplasia of the remaining epithelium in response to chronic inflammation, further diminishing mucociliary clearance. In some instances, necrosis destroys the bronchial or bronchiolar walls and forms a lung abscess. Fibrosis of the bronchial and bronchiolar walls and peribronchiolar fibrosis develop in more chronic cases, leading to varying degrees of subtotal or total obliteration of bronchiolar lumens.

Haemophilus influenzae is found in approximately half and Pseudomonas aeruginosa in 12% to 30% of sputum cultures from patients with bronchiectasis, with four other types of bacteria (including non-tuberculous mycobacteria) making up most of the remaining cases in patients from different geographic locations. This observation suggests that the inflamed, mucoid, sometimes anaerobic, bronchiectatic microenvironment favors colonization by a relatively few microbial species. In allergic bronchopulmonary aspergillosis, fungal hyphae can be seen on special stains within the mucoinflammatory contents of the dilated segmental bronchi. In late stages the fungus may infiltrate the bronchial wall.

Clinical Features

Bronchiectasis causes severe, persistent cough; expectoration of foul smelling, sometimes bloody sputum; dyspnea and orthopnea in severe cases; and, on occasion, hemoptysis, which may be massive. Symptoms are often episodic and are precipitated by upper respiratory tract infections or the introduction of new pathogenic agents. Paroxysms of cough are particularly frequent when the patient rises in the morning, as the change in position causes collections of pus and secretions to drain into the bronchi. Obstructive respiratory insufficiency can lead to marked dyspnea and cyanosis. However, current treatments with better antibiotics and physical therapy have improved outcomes considerably, and life expectancy has almost doubled. Hence, cor pulmonale, brain abscesses, and amyloidosis are less frequent complications of bronchiectasis currently than in the past.

Pathogenesis

While the cause of IPF remains unknown, it appears that it arises in genetically predisposed individuals who are prone to aberrant repair of recurrent alveolar epithelial cell injuries caused by environmental exposures ( Fig. 15.13 ). The implicated factors are as follows:

• Environmental factors. Most important among these is cigarette smoking, which increases the risk of IPF several-fold. IPF incidence is also increased in individuals who are exposed to air pollution, microaspiration, metal fumes, and wood dust, or who work in certain occupations, including farming, hairdressing, and stone polishing. It is hypothesized that exposure to environmental irritants or toxins in each of these contexts causes recurrent alveolar epithelial cell damage.

• Genetic factors. The vast majority of individuals who smoke or who have other environmental exposures linked to IPF do not develop the disorder, indicating that additional factors are required for its development. Mutations in the TERT, TERC, PARN, and RTEL1 genes, all of which are involved with the maintenance of telomeres, are associated with increased risk of IPF. You will recall that maintenance of telomeres (the ends of chromosomes) is necessary to prevent cellular senescence. Up to 15% of familial IPF is associated with inherited defects in genes that maintain telomeres, while up to 25% of sporadic IPF cases are associated with abnormal telomere shortening in peripheral blood lymphocytes, a finding that also points to a problem with telomere maintenance. Other, rare familial forms of IPF are associated with mutations in genes encoding components of surfactant; these mutations create folding defects in the affected proteins, leading to activation of the unfolded protein response in type II pneumocytes. This in turn appears to make pneumocytes more sensitive to environmental insults, leading to cellular dysfunction and injury. Finally, roughly one-third of IPF cases are associated with a single-nucleotide polymorphism in the promoter of the MUC5B gene that greatly increases the secretion of MUC5B, a member of the mucin family. This may in turn alter mucociliary clearance, but precisely how this alteration relates to IPF risk is uncertain.

• Age. IPF is a disease of older individuals, rarely appearing before the age of 50 years. Whether this association stems from aging-related telomere shortening or from other acquired changes associated with aging is unknown.

It is easy to imagine how some of the factors cited herein might combine to exacerbate alveolar epithelial cell damage and senescence, which seems to be the initiating event in IPF, but it must be admitted that the pathogenesis of IPF is complex and poorly understood. For example, it is unknown precisely how alveolar epithelial cell damage translates into interstitial fibrosis. One model holds that the injured epithelial cells are the source of profibrogenic factors such as TGF-β, whereas a second, non–mutually exclusive model proposes that innate and adaptive immune cells produce such factors as part of the host response to epithelial cell damage. Other work has described abnormalities in the fibroblasts themselves that involve changes in intracellular signaling and features reminiscent of epithelial mesenchymal transition ( Chapter 7 ), but a causal link between these alterations and fibrosis has not been established.

Morphology

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 firm, rubbery white areas of fibrosis, which occurs preferentially in the lower lobes, the subpleural regions, and along the interlobular septa. Microscopically, the hallmark is patchy interstitial fibrosis, which varies in intensity ( Fig. 15.14 ) and age. The earliest lesions contain an exuberant proliferation of fibroblasts (fibroblastic foci) . With time these areas become more fibrotic 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 the 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 fibrosis and fibroblastic foci) can be identified even in advanced IPF. There is mild to moderate inflammation within the fibrotic areas, consisting of mostly lymphocytes admixed with a few plasma cells, neutrophils, eosinophils, and mast cells. Foci of squamous metaplasia and smooth muscle hyperplasia may be present, along with pulmonary arterial hypertensive changes (intimal fibrosis and medial thickening). In acute exacerbations, DAD may be superimposed on these chronic changes.

Clinical Features

IPF begins insidiously with gradually increasing dyspnea on exertion and dry cough. Most patients are 55 to 75 years old at presentation. Hypoxemia, cyanosis, and clubbing occur late in the course. The course in individual patients is unpredictable. Usually there is slowly progressive respiratory failure, but some patients have acute exacerbations and follow a rapid downhill clinical course. The median survival is about 3.8 years after diagnosis. Lung transplantation is the only definitive therapy; however, two drugs, a tyrosine kinase inhibitor and a TGF-β antagonist, have both been shown to slow disease progression and represent the first effective (albeit modestly so) targeted therapies for IPF.

Clinical Features

Patients present with dyspnea and cough of several months’ duration. They are more likely to be female nonsmokers in their sixth decade of life. On imaging, the lesions have the appearance of bilateral, symmetric, predominantly lower lobe reticular opacities. Patients having the cellular pattern are somewhat younger than those with the fibrosing pattern and have a better prognosis.

Pathogenesis

Specific factors that influence the development of dust-borne pneumoconiosis include the following:

• Dust retention, which 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 impairs mucociliary clearance significantly increases the accumulation of dust in the lungs.

• Particle size. The most dangerous particles are from 1 to 5 µm in diameter because particles of this size can reach the terminal small airways and air sacs and deposit in their linings.

• Particle solubility and cytotoxicity, which are influenced by particle size. In general, small particles composed of injurious substances of high solubility are more likely to produce rapid-onset acute lung injury. By contrast, larger particles are more likely to resist dissolution and may persist within the lung parenchyma for years. These tend to evoke fibrosing collagenous pneumoconioses, such as is characteristic of silicosis.

• Particle uptake by epithelial cells or egress across epithelial linings, which allows direct interactions with fibroblasts and interstitial macrophages to occur. Some particles may reach the lymph nodes through lymphatic drainage directly or within migrating macrophages and thereby initiate an adaptive immune response to components of the particulates or to self-proteins modified by the particles or both.

• Activation of the inflammasome ( Chapter 3 ), which occurs following the phagocytosis of certain particles by macrophages. This innate immune response amplifies the intensity and the duration of the local reaction.

• Tobacco smoking, which worsens the effects of all inhaled mineral dusts, but particularly those caused by asbestos.

In general, only a small percentage of exposed people develop occupational respiratory diseases, implying a genetic predisposition to their development. Many of the diseases listed in Table 15.6 are quite uncommon; hence only a select few that cause pulmonary fibrosis are presented next.

Coal Workers’ Pneumoconiosis

Coal workers’ pneumoconiosis is lung disease caused by inhalation of coal particles and other admixed forms of dust. Dust reduction measures in coal mines around the globe have drastically reduced its incidence. The spectrum of lung findings in coal workers is wide, varying from asymptomatic anthracosis, to simple coal workers’ pneumoconiosis with little to no pulmonary dysfunction, to complicated coal workers’ pneumoconiosis, or progressive massive fibrosis, in which lung function is compromised. Contaminating silica in the coal dust favors the development of progressive disease. In most cases, carbon dust itself is the major culprit, and studies have shown that complicated lesions contain much more dust than simple lesions. Coal workers may also develop emphysema and chronic bronchitis independent of smoking.

Morphology

Carbon deposits are dark black in color and are readily visible grossly and microscopically. Anthracosis is the most innocuous coal-induced pulmonary lesion in coal miners and is also seen to some degree in urban dwellers and tobacco smokers. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which accumulate in the connective tissue adjacent to the lymphatics and in organized lymphoid tissue adjacent to the bronchi or in the lung hilus.

Simple coal workers’ pneumoconiosis is characterized by coal macules (1 to 2 mm in diameter) and somewhat larger coal nodules. Coal macules consist of carbon-laden macrophages; nodules also contain a delicate network of collagen fibers. Although these lesions are scattered throughout the lung, the upper lobes and upper zones of the lower lobes are more heavily involved. They are located primarily adjacent to respiratory bronchioles, the site of initial dust accumulation. In due course dilation of adjacent alveoli occurs, sometimes giving rise to centrilobular emphysema.

Complicated coal workers’ pneumoconiosis (progressive massive fibrosis) occurs on a background of simple disease and generally requires many years to develop. It is characterized by intensely blackened scars 1 cm or larger, sometimes up to 10 cm in greatest diameter. They are usually multiple. Microscopically, the lesions consist of dense collagen and pigment ( Fig. 15.17 ). The center of the lesion is often necrotic, most likely due to local ischemia.

Clinical Features

Coal workers’ pneumoconiosis is usually benign, causing little decrement in lung function. Even mild forms of complicated coal workers’ pneumoconiosis do not affect lung function significantly. In a minority of cases (fewer than 10%), progressive massive fibrosis develops, leading to increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale. Once progressive massive fibrosis develops, it may continue to worsen even if further exposure to dust is prevented. Unlike silicosis (discussed next), there is no convincing evidence that coal workers' pneumoconiosis increases susceptibility to tuberculosis, nor does it predispose to cancer in the absence of smoking. However, domestic indoor use of “smoky coal” (bituminous) for cooking and heating, a common practice in lower income parts of the world, is associated with an increased risk of lung cancer death, even in those who do not smoke.

Silicosis

Silicosis is a common lung disease caused by inhalation of proinflammatory crystalline silicon dioxide (silica). It usually presents after decades of exposure as slowly progressing, nodular, fibrosing pneumoconiosis. Currently, silicosis is the most prevalent chronic occupational disease in the world. Both dose and race are important in developing silicosis (African Americans are at higher risk than Caucasians). As shown in Table 15.6 , workers in a large number of occupations are at risk, including individuals involved with the repair, rehabilitation, or demolition of concrete structures such as buildings and roads. The disease also occurs in workers producing stressed denim by sandblasting, stone carvers, and jewelers using chalk molds. Occasionally, heavy exposure over months to a few years can result in acute silicosis, a disorder characterized by the accumulation of abundant lipoproteinaceous material within alveoli (identical morphologically to alveolar proteinosis, discussed later).

Pathogenesis

Phagocytosis of inhaled silica crystals by macrophages activates the inflammasome and stimulates the release of inflammatory mediators, particularly IL-1 and IL-18. This in turn leads to the recruitment of additional inflammatory cells and activates interstitial fibroblasts, leading to collagen deposition. Silica occurs in both crystalline and amorphous forms, but crystalline forms (including quartz, cristobalite, and tridymite) are much more fibrogenic. Of these, quartz is most commonly implicated. The lack of severe responses to silica in coal and hematite miners is thought to be due to coating of silica with other minerals, especially clay components, which render the silica less toxic. Although amorphous silicates are biologically less active than crystalline silica, heavy lung burdens of these minerals may also produce lesions.

Morphology

Silicosis is characterized grossly in its early stages by tiny, barely palpable, discrete pale to blackened (if coal dust is also present) nodules in the hilar lymph nodes and upper zones of the lungs. As the disease progresses, these nodules coalesce into hard, collagenous scars ( Fig. 15.18 ). Some nodules may undergo central softening and cavitation due to superimposed tuberculosis or to ischemia. Fibrotic lesions may also occur in the hilar lymph nodes and pleura. Sometimes, thin sheets of calcification occur in the lymph nodes and are seen radiographically as eggshell calcification (i.e., calcium surrounding a zone lacking calcification). If the disease continues to progress, expansion and coalescence of lesions may produce progressive massive fibrosis. Histologic examination reveals the hallmark lesion characterized by a central area of whorled collagen fibers with a more peripheral zone of dust-laden macrophages ( Fig. 15.19 ). Examination of the nodules by polarized microscopy reveals weakly birefringent silicate particles.

Clinical Features

The onset of silicosis may be slow and insidious (10 to 30 years after exposure; this is most common), accelerated (within 10 years of exposure), or rapid (weeks or months after intense exposure to fine dust high in silica; this is rare). Chest radiographs typically show a fine nodularity in the upper zones of the lung. Pulmonary function is either normal or only moderately affected early in the course, and most patients do not develop shortness of breath until progressive massive fibrosis supervenes. The disease may continue to worsen even if the patient is no longer exposed. It is slow to kill, but impaired pulmonary function may severely limit activity.

Silicosis also is associated with an increased susceptibility to tuberculosis and a twofold increased risk of lung cancer. The former may be because crystalline silica inhibits the ability of pulmonary macrophages to kill phagocytosed mycobacteria. The link to cancer is not fully understood, but it is but one of many chronic inflammatory conditions that increase the risk of carcinoma in involved tissues ( Chapter 7 ).

Asbestos-Related Diseases

Asbestos is a family of proinflammatory crystalline hydrated silicates that are associated with pulmonary fibrosis and various forms of cancer. Use of asbestos is tightly restricted in many higher income countries; however, there is little, if any, control in lower income parts of the world. Asbestos-related diseases include:

• Localized fibrous plaques or, rarely, diffuse pleural fibrosis

• Pleural effusions, recurrent

• Parenchymal interstitial fibrosis (asbestosis)

• Lung carcinoma

• Mesothelioma

• Laryngeal, ovarian, and perhaps other extrapulmonary neoplasms, including colon carcinoma

• Increased risks for systemic autoimmune diseases and cardiovascular disease also have been proposed

The increased incidence of asbestos-related cancers in family members of asbestos workers has alerted the general public to the potential hazards of even low-level exposure to asbestos. However, the necessity of expensive asbestos abatement programs for environments such as schools with low, but measurable, airborne asbestos fiber counts remains a matter of contention.

Pathogenesis

The disease-causing capabilities of the different forms of asbestos depend on concentration, size, shape, and solubility. Asbestos occurs in two distinct geometric forms, serpentine and amphibole. The serpentine chrysotile form accounts for 90% of the asbestos used in industry. Amphiboles, even though less prevalent, are more pathogenic than chrysotiles, particularly with respect to induction of mesothelioma, a malignant tumor derived from the lining cells of pleural surfaces (described later).

The greater pathogenicity of amphiboles is apparently related to their aerodynamic properties and solubility. Chrysotiles, with their more flexible, curled structure, are likely to become impacted in the upper respiratory passages and removed by the mucociliary elevator. Furthermore, once trapped in the lungs, chrysotiles are gradually leached from the tissues because they are more soluble than amphiboles. In contrast, the straight, stiff amphiboles may align themselves with the airstream and thus be delivered deeper into the lungs, where they can penetrate epithelial cells and reach the interstitium. Both amphiboles and serpentines are fibrogenic, and increasing doses are associated with a higher incidence of asbestos-related diseases.

In contrast to other inorganic dusts, asbestos acts as a tumor initiator and a tumor promoter ( Chapter 7 ). Some of its oncogenic effects are mediated by reactive free radicals generated by asbestos fibers, which preferentially localize in the distal lung, close to the mesothelial cells of the pleura. Toxic chemicals adsorbed onto the asbestos fibers also likely contribute to the oncogenicity of the fibers. For example, the adsorption of carcinogens in tobacco smoke onto asbestos fibers may be the basis for the remarkable synergy between tobacco smoking and the development of lung carcinoma in asbestos workers. Smoking also enhances the effect of asbestos by interfering with the mucociliary clearance of fibers. One study of asbestos workers found a fivefold increase of lung carcinoma with asbestos exposure alone, while asbestos exposure and smoking together led to a 55-fold increase in the risk.

Once phagocytosed by macrophages, asbestos fibers activate the inflammasome and stimulate the release of proinflammatory factors and fibrogenic mediators. The initial injury occurs at bifurcations of small airways and ducts, where asbestos fibers land, penetrate, and are directly toxic to pulmonary parenchymal cells. Macrophages, both alveolar and interstitial, attempt to ingest and clear the fibers. Long-term deposition of fibers and persistent release of mediators (e.g., reactive oxygen species, proteases, cytokines, and growth factors) eventually lead to generalized interstitial pulmonary inflammation and fibrosis.

Morphology

Asbestosis is marked by diffuse pulmonary interstitial fibrosis, which is distinguished from diffuse interstitial fibrosis resulting from other causes only by the presence of asbestos bodies. Asbestos bodies are golden brown, fusiform or beaded rods with a translucent center that consist of asbestos fibers coated with an iron-containing proteinaceous material ( Fig. 15.20 ). They arise when macrophages phagocytose asbestos fibers; the iron is presumably derived from phagocyte ferritin. Other inorganic particulates may become coated with similar iron-protein complexes and are called ferruginous bodies.

Asbestosis begins as fibrosis around respiratory bronchioles and alveolar ducts and extends to involve adjacent alveolar sacs and alveoli. The fibrosis distorts the architecture, creating enlarged airspaces enclosed by thick fibrous walls; eventually the affected regions become honeycombed. The pattern of fibrosis is histologically similar to that seen in usual interstitial fibrosis, with fibroblastic foci and varying degrees of fibrosis. In contrast to coal workers’ pneumoconiosis and silicosis, asbestosis begins in the lower lobes and subpleurally, with the middle and upper lobes becoming affected as fibrosis progresses. The scarring may trap and narrow pulmonary arteries and arterioles, causing pulmonary hypertension and cor pulmonale.

Pleural plaques, the most common manifestation of asbestos exposure, are well-circumscribed plaques of dense collagen that are often calcified ( Fig. 15.21 ). They develop most frequently on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm. The size and number of pleural plaques do not correlate with the level of exposure to asbestos or the time since exposure. They also do not contain identifiable asbestos bodies; however, only rarely do they occur in individuals without a history or evidence of asbestos exposure. Uncommonly, asbestos exposure induces pleural effusions, which are usually serous but may be bloody. Rarely, diffuse visceral pleural fibrosis may occur and, in advanced cases, bind the lung to the thoracic wall.

Both lung carcinomas and mesotheliomas (pleural and peritoneal) develop in workers exposed to asbestos (see sections on Carcinomas and Pleural Tumors ).

Clinical Features

The clinical findings in asbestosis are very similar to those caused by other diffuse interstitial lung diseases (discussed earlier). They rarely appear fewer than 10 years after first exposure and are more common after 20 to 30 years. Dyspnea is usually the first manifestation; at first, it is provoked by exertion, but later is present even at rest. Cough associated with production of sputum, when present, is likely to be due to smoking rather than asbestosis. Chest x-ray studies reveal irregular linear densities, particularly in both lower lobes. With advancement of the pneumoconiosis, a honeycomb pattern develops. The disease may remain static or progress to respiratory failure, cor pulmonale, and death. Pleural plaques are usually asymptomatic and are detected on radiographs as circumscribed densities. Asbestosis complicated by lung or pleural cancer is associated with a particularly grim prognosis.

Key Concepts

Pneumoconioses

• Pneumoconioses encompass a group of chronic fibrosing diseases of the lung resulting from exposure to organic and inorganic particulates, most commonly mineral dust.

• Pulmonary alveolar macrophages play a central role in the pathogenesis of lung injury by promoting inflammation and producing fibrogenic cytokines.

• Coal dust–induced disease varies from asymptomatic anthracosis to simple coal workers’ pneumoconiosis (coal macules or nodules, and centrilobular emphysema), to progressive massive fibrosis, manifested by increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale.

• Silicosis is the most common pneumoconiosis in the world, and crystalline silica (e.g., quartz) is the usual culprit. The lung disease is progressive even after exposure stops.

• The manifestations of silicosis range from asymptomatic silicotic nodules to large areas of dense fibrosis; persons with silicosis also have an increased susceptibility to tuberculosis. There is twofold increased risk of lung cancer.

• Asbestos fibers come in two forms; the stiff amphiboles have a greater fibrogenic and carcinogenic potential than the serpentine chrysotiles.

• Asbestos exposure is linked with six disease processes: (1) parenchymal interstitial fibrosis (asbestosis); (2) localized pleural plaques (asymptomatic) or rarely diffuse pleural fibrosis; (3) recurrent pleural effusions; (4) lung carcinoma; (5) malignant pleural and peritoneal mesotheliomas; and (6) laryngeal cancer.

• Cigarette smoking increases the risk of lung cancer in the setting of asbestos exposure; even family members of workers exposed to asbestos are at increased risk for lung carcinoma and mesothelioma.