Robbins Pathology PDF - Chapter 11: Lung

CHAPTER 11 Lung 401 ALVEOLAR Type II pneumocyte is gradually absorbed, leading to alveolar collapse. The most com- SPACE mon cause of resorption atelectasis...

CHAPTER 11 Lung 401 ALVEOLAR Type II pneumocyte is gradually absorbed, leading to alveolar collapse. The most com- SPACE mon cause of resorption atelectasis is postoperative intrabronchial mucous or mucopurulent plugs, but it may also result from foreign body aspiration (particularly in children), bronchial asthma, bron- Type I chiectasis, chronic bronchitis, or intrabronchial tumor, in which it Endothelium pneumocyte Interstitial may be the first sign of malignancy. cell Compression atelectasis is caused by the accumulation of fluid, blood, or air within the pleural cavity. A frequent cause is pleural effusions in the setting of congestive heart failure. Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis. Basal atelectasis, resulting from a failure to breathe CAPILLARY deeply, commonly occurs in patients who are bedridden, in those LUMEN with ascites, and during and after surgery. Contraction atelectasis (or cicatrization atelectasis) occurs when local or diffuse pulmonary or pleural fibrosis hampers lung Type I pneumocyte expansion. ALVEOLAR SPACE Atelectasis (except when caused by contraction) is potentially Endothelium reversible and should be treated promptly to prevent hypoxemia and FIG. 11.1 Microscopic structure of the alveolar wall. Note that the superimposed infection of the collapsed lung. basement membrane (yellow) is thin on one side and widened where it is continuous with the interstitial space. ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME right and two on the left. The main bronchi branch to give rise to pro- gressively smaller airways, termed bronchioles, which are distinguished Acute lung injury (ALI) is characterized by the abrupt onset of from bronchi by the lack of cartilage and submucosal glands within their hypoxemia and bilateral pulmonary edema in the absence of cardiac walls. Further branching of bronchioles leads to terminal bronchioles; the failure (noncardiogenic pulmonary edema); if severe, ALI may lead part of the lung distal to the terminal bronchiole is called an acinus. to acute respiratory distress syndrome (ARDS). Both ARDS and ALI Pulmonary acini are composed of respiratory bronchioles (emanating are associated with inflammation-induced increases in pulmonary from the terminal bronchiole) that proceed into alveolar ducts, which vascular permeability, edema, and epithelial cell death. The histologic immediately branch into alveolar sacs, the blind ends of the respiratory manifestation of these conditions is diffuse alveolar damage. passages, whose walls are formed entirely of alveoli, the site of gas ex- The definition of acute respiratory distress syndrome (ARDS) is change. The alveolar walls (or alveolar septa) consist of the following evolving. Formerly considered to be the severe end of a spectrum of components, proceeding from blood to air (Fig. 11.1): acute lung injury, it is now defined as respiratory failure occurring The capillary endothelium and basement membrane within 1 week of a known clinical insult with bilateral opacities on The pulmonary interstitium, composed of fine elastic fibers, small chest imaging that are not fully explained by effusions, atelectasis, bundles of collagen, a few fibroblast-like cells, smooth muscle cells, cardiac failure, or fluid overload. It is graded based on the severity of mast cells, and rare mononuclear cells blood hypoxemia. Causes are diverse; the shared feature is that all lead Alveolar epithelium, consisting of a continuous layer of two principal to extensive bilateral alveolar injury. cell types: flattened, platelike type I pneumocytes covering 95% of the ARDS may occur in a multitude of clinical settings and is associ- alveolar surface and rounded type II pneumocytes. The latter synthe- ated with primary pulmonary diseases and severe systemic inflam- size pulmonary surfactant and are the main cell type involved in matory disorders such as sepsis. The most frequent triggers of ARDS repair of alveolar epithelium after damage to type I pneumocytes. are pneumonia (35%e45%) and sepsis (30%e35%) followed by aspiration, trauma (including brain injury, abdominal surgery, and A few alveolar macrophages usually lie free within the alveolar multiple fractures), pancreatitis, and transfusion reactions. Notably, space. In city dwellers, these macrophages often contain phagocytosed COVID-19 pneumonia (described later) progresses in a subset of carbon particles. patients to ARDS, which often requires intubation and mechanical Lung diseases can broadly be divided into those affecting the air- ventilation. ARDS should not be confused with respiratory distress ways, the interstitium, or the pulmonary vascular system. This division syndrome of the newborn; the latter is caused by a deficiency of into discrete compartments is deceptively simple, as disease in one surfactant in the setting of prematurity. compartment often causes secondary alterations of morphology and function in others. Pathogenesis. The underlying basis of ARDS is injury to the epithelial and endothelial linings of the alveolar-capillary mem- brane. Most research suggests that ARDS stems from an inflammatory ATELECTASIS (COLLAPSE) reaction initiated by proinflammatory mediators (Fig. 11.2). Release of Atelectasis is loss of lung volume caused by inadequate expansion of factors such as IL-1 and tumor necrosis factor (TNF) leads to air spaces. Because atelectatic lung continues to be perfused, it pro- endothelial activation and sequestration and activation of neutrophils duces a ventilation-perfusion imbalance and hypoxemia. On the basis in pulmonary capillaries. Neutrophils are thought to have an of the underlying mechanism and its anatomic, atelectasis is classified important role in the pathogenesis of ARDS. Histologic examination into three forms: of lungs early in the disease process shows increased numbers of Obstruction atelectasis occurs when an obstruction prevents air neutrophils within capillaries, the interstitium, and alveoli. Activated from reaching distal airways. Air present distal to the obstruction neutrophils release a variety of products (e.g., reactive oxygen 402 CHAPTER 11 Lung HEALTHY ALVEOLUS ACUTE LUNG INJURY Bronchial epithelium Sloughed bronchial epithelium Inactivated Necrotic type I cell Basement membrane surfactant Edema fluid Cytokines ROS Proteases Alveolar macrophage Cellular debris Surfactant layer TNF IL-1 Alveolus Neutrophil Fibrin sequestration Type I cell and migration into alveolus TNF Chemokines Hyaline Type II cell membrane Interstitium Fibroblast Capillary Procollagen Edema Endothelial cell Injured, swollen endothelial cells FIG. 11.2 Acute lung injury. The healthy alveolus (left) and the injured alveolus (right) in the early phase of acute lung injury and the acute respiratory distress syndrome. Under the influence of proinflammatory cyto- kines such as IL-1 and tumor necrosis factor (TNF) (released by macrophages), neutrophils are sequestered in the pulmonary microvasculature and then egress into the alveolar space, where they undergo activation. Activated neutrophils release mediators such as reactive oxygen species (ROS), cytokines, and proteases, which contribute to local tissue damage, accumulation of edema fluid, surfactant inactivation, and hyaline membrane formation. (Modified from Ware LB: Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med 27:337, 2006.) species, proteases) that damage the alveolar epithelium and respiratory distress syndrome of the newborn (Chapter 4). In the orga- endothelium. The assault on the endothelium and epithelium causes nizing stage, type II pneumocytes proliferate vigorously in an attempt to vascular leakiness and a loss of surfactant that stiffens the alveolar regenerate the alveolar lining. Complete resolution is unusual; more unit. Of note, the destructive forces unleashed by neutrophils can be commonly, the fibrin-rich exudates undergo organization, leading to fibrosis counteracted by an array of endogenous antiproteases and anti- and alveolar septal thickening. oxidants. In the end, it is the balance between these destructive and protective factors that determines the degree of tissue injury and clinical severity of ARDS. Clinical Features. It is estimated that acute lung injury or ARDS af- MORPHOLOGY fects approximately 200,000 patients per year in the United States. In 85% of cases, it develops within 72 hours of the initial insult. ARDS is In the acute phase of ARDS, the lungs are dark red, firm, airless, and the underlying disorder in a sizable minority of patients who require heavy. Microscopic examination reveals capillary congestion, necrotic mechanical ventilation. Imaging studies show bilateral ground glass alveolar epithelial cells, interstitial and intraalveolar edema and hemor- opacities (eFig. 11.1). Predictors of poor prognosis include advanced rhage, and (particularly with sepsis) collections of neutrophils in capillaries. age, bacteremia (sepsis), and the development of multiorgan failure. The most characteristic finding is the presence of hyaline membranes, The overall mortality rate is about 40%, with death usually stemming particularly lining the distended alveolar ducts (Fig. 11.3). Such membranes from the underlying condition or superimposed infection. Death from consist of fibrin-rich edema fluid admixed with remnants of necrotic respiratory failure is uncommon. Survivors frequently have decreased epithelial cells. Overall, the picture is remarkably similar to that seen in physical endurance due in part to lung function abnormalities.  CHAPTER 11 Lung 402.e1 eFIG. 11.1 Diffuse alveolar damage, CT scan. Extensive bilateral “bright” ground glass opacities are seen. (From Klatt EC: Robbins and Cotran Atlas of Pathology, ed 4, Fig. 5.14, Philadelphia, 2021, Elsevier.)  CHAPTER 11 Lung 403 OBSTRUCTIVE AND RESTRICTIVE PULMONARY DISEASES Diffuse pulmonary diseases can be classified into two categories: (1) obstructive (airway) disease, characterized by an increase in resis- tance to air flow caused by partial or complete obstruction at any level; and (2) restrictive disease, marked by reduced expansion of lung parenchyma, and decreased total lung capacity. The major diffuse obstructive disorders are emphysema, chronic bronchitis, bronchiectasis, and asthma. In patients with these diseases, the expiratory flow rate, measured as the forced expiratory volume at 1 second (FEV1), is significantly decreased, whereas forced vital capacity (FVC) is either normal or slightly decreased. Thus, the ratio of FEV1 to FVC is decreased. An FEV1/FVC ratio of less than 0.7 generally in- dicates the presence of obstructive disease. Expiratory obstruction may result from airway narrowing, classically observed in asthma, or from loss of elastic recoil, seen in emphysema. A By contrast, in diffuse restrictive diseases, FVC is reduced and the expiratory flow rate is normal or reduced proportionately. Hence, the ratio of FEV1 to FVC is near normal. Restrictive diseases fall into two broad categories: (1) disorders of chest wall expansion in the presence of normal lungs (e.g., severe obesity, diseases of the pleura, and neuro- muscular disorders, such as the Guillain-Barré syndrome [Chapter 20]) and (2) acute or chronic interstitial lung diseases. The classic acute restrictive disease is ARDS, discussed earlier. Chronic restrictive diseases (discussed later) include the pneumoconioses, interstitial fibrosing dis- orders, and infiltrative conditions such as sarcoidosis. OBSTRUCTIVE LUNG (AIRWAY) DISEASES In their prototypical forms, the four major disorders in this groupd emphysema, chronic bronchitis, asthma, and bronchiectasisdhave B distinct clinical and anatomic characteristics (Table 11.1). However, FIG. 11.3 Acute lung injury and acute respiratory distress syndrome. emphysema and chronic bronchitis cooccur so frequently that they are (A) Diffuse alveolar damage in the acute phase. Some alveoli are typically considered together under the rubric of chronic obstructive collapsed, while others are distended; many are lined by bright pink pulmonary disease. Their close association is not surprising, as ciga- hyaline membranes (arrow). (B) The healing stage is marked by resorp- rette smoking is the major underlying cause of both emphysema and tion of hyaline membranes and thickening of alveolar septa by inflam- chronic bronchitis. matory cells, fibroblasts, and collagen. Numerous reactive type II pneumocytes (arrows) also are seen at this stage, associated with Chronic Obstructive Pulmonary Disease regeneration and repair. Chronic obstructive pulmonary disease (COPD), a major public health problem, is defined by the World Health Organization Table 11.1 Disorders Associated With Airflow Obstruction Anatomic Clinical Entity Site Major Pathologic Changes Etiology Signs/Symptoms Emphysema Acinus Air space enlargement, wall destruction Tobacco smoke Dyspnea Chronic bronchitis Bronchus Mucous gland hypertrophy and Tobacco smoke, air pollutants Cough, sputum production hyperplasia, hypersecretion Bronchiectasis Bronchus Airway dilation and scarring Persistent or severe Cough, purulent sputum, infections fever Asthma Bronchus Smooth muscle hypertrophy and Immunologic or undefined Episodic wheezing, cough, hyperplasia, excessive mucus, causes dyspnea inflammation Small airway Bronchiole Inflammatory scarring, partial obliteration Tobacco smoke, air pollutants Cough, dyspnea disease, of bronchioles bronchiolitisa a Can be present in all forms of obstructive lung disease or occur by itself. 404 CHAPTER 11 Lung (WHO) as “a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow Alveolus limitation that is due to airway and/or alveolar abnormalities caused by exposure to noxious particles or gases.” COPD affects more than 10% of the U.S. adult population over the age of 40 years. NORMAL ACINUS It is the fourth leading cause of death in this country, the third leading cause of death worldwide, and is rising in frequency due to increases Respiratory Alveolar bronchiole duct in cigarette smoking in parts of Africa and Asia. Overall, 35% to 50% of heavy smokers develop COPD; conversely, about 80% of COPD is attributable to smoking. Women appear to be more susceptible than men to developing COPD. Additional risk factors include poor lung development early in life, exposure to environmental and occupa- tional pollutants, airway hyperresponsiveness, and certain genetic polymorphisms. Although emphysema and chronic bronchitis often occur together as part of COPD, it is useful to discuss these patterns of lung injury A Alveolus and associated functional abnormalities individually to highlight the pathophysiologic basis of different causes of airflow obstruction Respiratory bronchiole Alveolar (Fig. 11.4). We will conclude our discussion by returning to the clinical duct features of COPD. Emphysema C Emphysema is characterized by permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by Panacinar emphysema destruction of their walls but without significant fibrosis. It is B classified according to its anatomic distribution. As discussed earlier, Centriacinar emphysema the acinus is the structure distal to terminal bronchioles, and a cluster FIG. 11.5 Major patterns of emphysema. (A) Diagram of normal of three to five acini is called a lobule (Fig. 11.5A). There are four structure of the acinus, the fundamental unit of the lung. (B) Centriacinar patterns of emphysema: (1) centriacinar, (2) panacinar, (3) distal emphysema with dilation that initially affects the respiratory bronchioles. acinar, and (4) irregular. Only the first two types are associated with (C) Panacinar emphysema with initial distention of all the peripheral COPD, with centriacinar emphysema being about 20 times more structures (i.e., the alveolus and alveolar duct); the disease later extends common than panacinar disease. to affect the respiratory bronchioles. Centriacinar (centrilobular) emphysema. The distinctive feature of centriacinar emphysema is involvement of the central or proximal parts of the acini with sparing of the distal alveoli. Thus, both involved, making it difficult to differentiate from panacinar emphysematous and normal air spaces exist within the same emphysema. Centroacinar emphysema is most common in indi- acinus and lobule (Fig. 11.5B). The lesions are more common viduals who smoke cigarettes, in whom it is often accompanied and severe in the upper lobes, particularly in the apical segments. by chronic bronchitis. In advanced centriacinar emphysema the distal acinus is also Panacinar (panlobular) emphysema. In panacinar emphysema, the acini are uniformly enlarged, from the level of the respiratory bron- chiole to the terminal blind alveoli (Fig. 11.5C). In contrast to cen- Chronic injury (e.g., smoking) triacinar emphysema, panacinar emphysema occurs more commonly in the lower lung zones and is associated with a1- Small airway disease antitrypsin deficiency. Distal acinar (paraseptal) emphysema. In this form of emphysema, the part of the acinus distal to the respiratory bronchiole is primar- EMPHYSEMA CHRONIC BRONCHITIS Alveolar wall destruction Productive cough ily affected. It tends to be found near the pleura, along the lobular Overinflation Airway inflammation connective tissue septa, and at the margins of the lobules adjacent to areas of fibrosis, scarring, or atelectasis, and is usually more se- vere in the upper half of the lungs. The characteristic finding is multiple enlarged air spaces ranging in diameter from less than 0.5 mm to more than 2.0 cm, sometimes forming cystic structures, ASTHMA that with further enlargement give rise to bullae. The cause is un- Reversible obstruction known; it comes to attention most often in young adults who pre- sent with spontaneous pneumothorax. Bronchial hyperresponsiveness Irregular emphysema. Irregular emphysema, so named because the triggered by allergens, infection, etc. acinus is irregularly involved, is almost invariably associated with scarring. In most cases it occurs in small foci and is clinically insignificant. FIG. 11.4 Schematic representation of overlap between chronic ob- Pathogenesis. Inhaled cigarette smoke and other noxious particles structive lung diseases. cause lung damage and inflammation, which, particularly in patients  CHAPTER 11 Lung 405 bronchioles to collapse during expiration. This leads to functional Smoking or air pollutant Congenital airflow obstruction in the absence of mechanical obstruction. + ␣1-antitrypsin genetic predisposition deficiency MORPHOLOGY The diagnosis and classification of emphysema depend largely on the macroscopic appearance of the lung. Typical panacinar emphysema produces pale, voluminous lungs that often obscure the heart when the Oxidative stress, Inflammatory Protease– increased cells, release of anterior chest wall is removed at autopsy. The macroscopic features of antiprotease apoptosis and inflammatory imbalance centriacinar emphysema are less impressive. Until late stages, the senescence mediators lungs are a deeper pink than in panacinar emphysema and less voluminous; the upper two-thirds of the lungs are more severely affected than the lower lungs. Histologic examination reveals destruction of alveolar walls without fibrosis, leading to enlarged air spaces (Fig. 11.7). Due Alveolar wall destruction to alveolar loss, the number of alveolar capillaries is diminished. Terminal and respiratory bronchioles may be deformed because of the loss of septa that FIG. 11.6 Pathogenesis of emphysema. See text for details. tether these structures in the parenchyma. Bronchiolar inflammation and submucosal fibrosis are often present in advanced disease. with a genetic predisposition, result in parenchymal destruction. Factors that influence the development of emphysema include the following (Fig. 11.6): Chronic Bronchitis Inflammatory cells and mediators: A wide variety of inflammatory Chronic bronchitis is defined by the presence of a persistent pro- mediators have been implicated (including leukotriene B4, the che- ductive cough for at least 3 consecutive months in at least 2 mokine IL-8, the cytokine tumor necrosis factor [TNF], and consecutive years. Thus its definition is based on clinical features, as others). These serve to recruit additional inflammatory cells from opposed to emphysema which is defined anatomically. It is common the circulation (chemotactic factors), amplify the inflammatory among people who smoke cigarettes and urban dwellers in smog- process (proinflammatory cytokines), and induce structural ridden cities. In early stages of chronic bronchitis, the cough pro- changes (growth factors). The inflammatory cells present in lesions duces mucoid sputum, but airflow is not obstructed. Some patients include neutrophils, macrophages, and CD4þ and CD8þ T cells. It with chronic bronchitis have evidence of hyperresponsive airways, is not known what antigens the T cells are specific for. with intermittent bronchospasm and wheezing (asthmatic bronchitis), Proteaseeantiprotease imbalance: Several proteases are released while other patients with bronchitis, especially those who smoke from the inflammatory cells and epithelial cells that break down heavily, develop chronic outflow obstruction, usually with associated connective tissues. In patients who develop emphysema, there is emphysema. a relative deficiency of protective antiproteases (discussed below). Oxidative stress: Reactive oxygen species are present in cigarette Pathogenesis. The distinctive feature of chronic bronchitis is hy- smoke, which also contains particles and other substances that persecretion of mucus, beginning in the large airways. Although the stimulate the release of additional reactive oxygen species from in- most important cause is cigarette smoking, other air pollutants, such flammatory cells such as macrophages and neutrophils. These cause as sulfur dioxide and nitrogen dioxide, may contribute. These tissue damage and inflammation (Chapter 2). Airway infection: Although infection is not thought to play a role in the initiation of tissue destruction, bacterial and/or viral infections cause acute exacerbations. The idea that proteases are important is based in part on the observation that an inherited deficiency of the antiprotease a1- antitrypsin predisposes to emphysema, an effect that is com- pounded by smoking. About 1% of patients with emphysema have this defect. a1-antitrypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases (particularly elas- tase) secreted by neutrophils during inflammation. It is encoded by the proteinase inhibitor (Pi) locus on chromosome 14. The Pi locus is polymorphic, and approximately 0.01% of the U.S. population is ho- mozygous for the Z allele, a genotype that is associated with markedly decreased serum levels of a1-antitrypsin. More than 80% of these individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and is of greater severity if the individual smokes. Protease-mediated damage of extracellular matrix has a central role in the airway obstruction seen in emphysema. Small airways are normally held open by the elastic recoil of the lung parenchyma, and FIG. 11.7 Pulmonary emphysema. There is marked enlargement of the the loss of elastic tissue in the walls of alveoli that surround respiratory air spaces, with destruction of alveolar septa but without fibrosis. Note bronchioles reduces radial traction and thus causes the respiratory the presence of black anthracotic pigment (arrows). 406 CHAPTER 11 Lung environmental irritants induce (1) hypertrophy of mucous glands in the Clinical Features of Chronic Obstructive Pulmonary Disease. Dyspnea trachea and bronchi; (2) an increase in mucin-secreting goblet cells in the is usually the first symptom; it begins insidiously but is often steadily epithelial surfaces of smaller bronchi and bronchioles; and (3) progressive. In patients with underlying chronic bronchitis or chronic inflammation marked by the infiltration of macrophages, neutrophils, asthmatic bronchitis, cough and wheezing may be the initial symp- and lymphocytes. In contrast with asthma (described later), eosinophils toms. Weight loss is common and may be sufficiently severe to suggest are not seen in chronic bronchitis. Whereas the mucus hypersecretion an occult malignant tumor. Pulmonary function tests reveal reduced primarily involves the large bronchi, the airflow obstruction in chronic FEV1 with normal or near-normal FVC. Hence, the FEV1 to FVC bronchitis results from small airway disease (chronic bronchiolitis) ratio is reduced. induced by mucous plugging of the bronchiolar lumen, inflammation, The classic presentation of emphysema with no “bronchitic” and bronchiolar wall fibrosis. component is one in which the patient is barrel-chested and dyspneic, It is postulated that many of the effects of environmental irritants with obviously prolonged expiration, sitting forward in a hunched- on respiratory epithelium are mediated by local release of cytokines over position. Imaging studies show hyperinflated lungs that such as IL-13 from T cells. The expression of mucins in bronchial “flatten” the diaphragm (eFig. 11.2). In such patients, air space epithelium and the production of neutrophil elastase are also enlargement is severe and diffusion capacity is low. Dyspnea and increased as a consequence of exposure to tobacco smoke. Microbial hyperventilation are prominent, so until very late in the disease, gas infection is often present but has a secondary role, chiefly by main- exchange is adequate and blood gas values are relatively normal. taining inflammation and exacerbating symptoms. Hypoxia-induced vascular spasm and loss of capillary surface area from alveolar destruction cause the gradual development of secondary MORPHOLOGY pulmonary hypertension, which in 20% to 30% of patients leads to Grossly, the mucosal lining of the larger airways is usually hyperemic right-sided congestive heart failure (cor pulmonale, Chapter 9). and swollen by edema fluid and is covered by a layer of mucinous or At the other end of the clinical spectrum is a patient with pro- mucopurulent secretions. The smaller bronchi and bronchioles may also nounced chronic bronchitis and a history of recurrent infections. The be filled with secretions. The diagnostic feature of chronic bronchitis in the course is quite variable. In some patients, cough and sputum pro- trachea and larger bronchi is enlargement of the mucus-secreting duction persist indefinitely without ventilatory dysfunction, while glands (Fig. 11.8). The magnitude of the increase in size is assessed by the others develop significant outflow obstruction. Dyspnea is usually less ratio of the thickness of the submucosal gland layer to that of the bronchial prominent than in those with “pure” emphysema, and in the absence wall (the Reid indexdnormally 0.4). Variable numbers of inflammatory cells, of increased respiratory drive the patient may retain carbon dioxide, largely lymphocytes and macrophages but sometimes also admixed neutro- becoming hypoxic and often cyanotic. The majority of patients with phils, are frequently seen in the bronchial mucosa. Chronic bronchio- this type of COPD are overweight or obese, which may further litis (small airway disease), characterized by goblet cell metaplasia, mucus decrease ventilation, particularly during sleep. Patients with severe plugging, inflammation, and fibrosis, is also seen. In severe cases, there may chronic bronchitis have more frequent exacerbations, more rapid be complete obliteration of the lumen as a consequence of fibrosis disease progression, and poorer outcomes than those with emphysema (bronchiolitis obliterans). It is the submucosal fibrosis that leads to alone. Progressive COPD is marked by the development of pulmonary luminal narrowing and airway obstruction. Emphysematous changes often hypertension, sometimes leading to cardiac failure (Chapter 9); coexist. recurrent infections; and ultimately respiratory failure. Approximately 10% to 30% of patients have obstructive sleep apnea; the pathogenic relationship between these two disorders is incompletely understood. Emphysematous Conditions Other Than COPD Several other conditions marked by abnormal air spaces or accumu- lations of air within the lungs or other tissues merit brief mention: Compensatory emphysema is the dilation of residual alveoli in response to loss of lung substance elsewhere, such as through sur- gical removal of a diseased lung or lobe. Obstructive overinflation is expansion of the lung due to air trap- ping. A common cause is subtotal obstruction of an airway by a tumor or foreign object. Obstructive overinflation may be life threatening if expansion of the affected portion produces compres- sion of the remaining normal lung. Bullous emphysema refers to large subpleural blebs or bullae (spaces >1 cm in diameter in the distended state) (Fig. 11.9). Such blebs stem from a localized accentuation of one of the four forms of pulmonary emphysema (discussed previously); most often the blebs are subpleural and prone to rupture, leading to pneumothorax. Mediastinal (interstitial) emphysema is caused by entry of air into FIG. 11.8 Chronic bronchitis. The lumen of the bronchus is above. Note the interstitium of the lung, from where it may then track to the the marked thickening of the mucous gland layer (approximately twice mediastinum and sometimes the subcutaneous tissue. It may occur normal) and squamous metaplasia (arrow) of lung epithelium. (From the when a sudden increase in intraalveolar pressure (as with vomiting Teaching Collection of the Department of Pathology, University of Texas, or violent coughing) causes alveolar rupture, allowing air to dissect Southwestern Medical School, Dallas, Texas.) into the interstitium. It may also occur in patients on respirators  CHAPTER 11 Lung 406.e1 eFIG. 11.2 Emphysema. A chest x-ray shows hyperinflated lungs that flatten the diaphragm (arrow). (From Klatt EC: Robbins and Cotran Atlas of Pathology, ed 4, Fig. 5.18, Philadelphia, 2021, Elsevier.)  CHAPTER 11 Lung 407 Both atopic and nonatopic forms of asthma are caused by activa- tion of mast cells and eosinophils, which release mediators that induce bronchoconstriction, inflammation, and mucus production. The dif- ference lies in how these are triggereddby immune mechanisms involving Th2 cells and IgE in the atopic form (discussed below) and by infection or nonimmunologic stimuli in the nonatopic form. Asthma shows familial clustering, but the role of genetics in asthma is complex. Genome-wide association studies have identified a large number of genetic variants associated with asthma risk, some in genes encoding factors like the IL-4 receptor that are clearly involved in asthma pathogenesis. However, the precise contribution of asthma- associated genetic variants to the development of disease remains to be determined. Atopic Asthma This is the most common type of asthma and is a classic example of FIG. 11.9 Bullous emphysema with large apical and subpleural bullae. type I IgE-mediated hypersensitivity reaction (Chapter 5). It usually (From the Teaching Collection of the Department of Pathology, Univer- begins in childhood. A positive family history of atopy and/or asthma sity of Texas Southwestern Medical School, Dallas, Texas.) is common, and the onset of asthmatic attacks is often preceded by allergic rhinitis, urticaria, or eczema. Attacks may be triggered by al- who have partial bronchiolar obstruction or in individuals with a lergens in dust, pollen, animal dander, or food, or by infections. The perforating injury (e.g., a fractured rib). If the interstitial air reaches diagnosis depends on the presence of typical episodic symptoms and the subcutaneous tissue, there can be marked swelling of the head documentation of airflow limitation that is corrected by treatment and neck and crackling crepitation (subcutaneous emphysema) over with bronchodilators. Skin testing with the offending antigen results in the chest. In most instances the air is resorbed spontaneously after an immediate wheal-and-flare reaction. In addition, immunoassays the site of entry seals. can be used to identify the presence of IgE antibodies that recognize specific allergens. Asthma The classic atopic form is associated with activation of type 2 Asthma is a chronic inflammatory disorder of the airways that causes helper T (Th2) cells, which release cytokines that account for most of recurrent episodes of bronchospasm characterized by wheezing, the observed featuresdspecifically, increased production of IgE from breathlessness, chest tightness, and cough, particularly at night and/or B cells (stimulated by IL-4 and IL-13); increased recruitment and early in the morning. The hallmarks of asthma are the following: activation of eosinophils (stimulated by IL-5); and increased mucus Intermittent, reversible airway obstruction production (stimulated by IL-13). IgE binds to Fc receptors on sub- Chronic bronchial inflammation with eosinophils mucosal mast cells, sensitizing these cells to allergens that cross-link Bronchial smooth muscle cell hypertrophy and hyperreactivity IgE molecules and stimulate the release of mast cell granule contents Increased mucus secretion and the secretion of cytokines and other mediators. These mediators set in motion events that lead to two waves of reaction, an early In patients with severe airway hyperreactivity, trivial stimuli may (immediate) phase and a late phase (Fig. 11.10): be sufficient to trigger attacks. Many cells play a role in the in- The early phase reaction is dominated by bronchoconstriction, flammatory response, in particular eosinophils, mast cells, macro- increased mucus production, and vasodilation. Bronchoconstric- phages, lymphocytes, neutrophils, and epithelial cells. Of note, tion is triggered by mediators released from mast cells, including asthma has increased in incidence significantly in more affluent histamine, prostaglandin D2, and leukotrienes C4, D4, and E4, countries over the past four decades. One proposed explanation for and also by reflex neural pathways. this trend is the hygiene hypothesis, according to which a lack of The late-phase reaction is inflammatory in nature. Inflammatory exposure to microbes and potential allergens in early childhood mediators stimulate epithelial cells to produce chemokines results in hyperreactivity to immune stimuli later in life. Attractive (including eotaxin, a potent chemoattractant of eosinophils) that as it seems, there is no mechanistic basis for this hypothesis. promote the recruitment of Th2 cells, eosinophils, and other leuko- cytes, thus amplifying an inflammatory reaction that is initiated by Pathogenesis. Major factors contributing to the development of resident immune cells. asthma include genetic predisposition to type I hypersensitivity Repeated bouts of inflammation lead to structural changes in the (atopy), acute and chronic airway inflammation, and bronchial bronchial wall that are collectively referred to as airway remodeling. hyperresponsiveness to a variety of stimuli. Asthma may be sub- These changes include hypertrophy of bronchial smooth muscle classified as atopic (marked by evidence of allergen sensitization) or and mucus glands and increased vascularity and deposition of sub- nonatopic. In both types, episodes of bronchospasm are triggered by epithelial collagen, which may occur several years before symptoms diverse exposures, such as respiratory infections (especially viral), begin. airborne irritants (e.g., smoke, fumes), and environmental stresses. There In addition, recent experimental work has shown that Charcot- are varying patterns of inflammationdeosinophilic (most common), Leyden crystals (eFig. 11.3), derived from a protein produced by neutrophilic, mixed inflammatory, and pauci-granulocyticdthat are eosinophils called galectin-10 and frequently seen in the airway associated with differing etiologies, immunopathologies, and responses mucous of patients with asthma, may be an important pro- to treatment. inflammatory factor.  CHAPTER 11 Lung 407.e1 eFIG. 11.3 Charcot-Leyden crystals. These reddish, needlelike crystals (arrowhead) are composed of galectin-10, a protein released from eosinophils. See text for details. (From Klatt EC: Robbins and Cotran Atlas of Pathology, ed 4, Fig. 5.33, Philadelphia, 2021, Elsevier.) 408 CHAPTER 11 Lung A HEALTHY AIRWAY B AIRWAY IN ASTHMA Mucus Mucus accumulation Goblet cells Goblet cell proliferation Epithelium Thickened subepithelial Basement basement membrane membrane Lamina propria Marked inflammation (eosinophil, macrophage, Smooth muscle lymphocyte, neutrophil) Submucosal Muscle cell hyperplasia glands and hypertrophy Cartilage Hypertrophy of submucosal glands C TRIGGERING OF ASTHMA D IMMEDIATE PHASE (MINUTES) E LATE PHASE (HOURS) Pollen Antigen Goblet Antigen cell (allergen) Mucus Mucus Dendritic cell Mucosal lining T-cell Eotaxin Major basic receptor Vagal afferent nerve protein Eosinophil IL-5 Mast cell Th2 cationic protein IL-5 Th2 cell Eosinophil IL-5 recruitment Th2 IL-4 Eosinophil IgE Fc receptor Increased vascular Mast cell IgE permeability Leukocyte recruitment B cell and edema Th2 Activation Basophil Eosinophil Neutrophil IgE antibody Smooth IgE secreting Vagal efferent nerve muscle plasma cell Release of granules and mediators Bronchoconstriction Bronchoconstriction FIG. 11.10 (A and B) Comparison of a healthy airway and an airway involved by asthma. The asthmatic airway is marked by accumulation of mucus in the bronchial lumen secondary to an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal glands; intense chronic inflam- mation due to recruitment of eosinophils, macrophages, and other inflammatory cells; thickened basement membrane; and hypertrophy and hyperplasia of smooth muscle cells. (C) Inhaled allergens (antigen) elicit a Th2-dominated response favoring IgE production and eosinophil recruitment. (D) On reexposure to antigen (Ag), the immediate reaction is triggered by antigen-induced crosslinking of IgE bound to Fc receptors on mast cells. These cells release mediators that directly and via neuronal reflexes induce bronchospasm, increased vascular permeability, mucus production, and recruitment of leukocytes. The latter (i.e., leukocyte recruitment) is the dominant finding in late phase reaction. (E) Leukocytes recruited to the site of reaction (neutrophils, eosinophils, and basophils; lymphocytes and monocytes) release additional mediators that initiate the late phase of asthma. Several factors released from eosinophils (e.g., major basic protein, eosinophil cationic protein) also cause damage to the epithelium.  CHAPTER 11 Lung 409 Nonatopic Asthma Patients with nonatopic forms of asthma do not have evidence of allergen sensitization, and skin test results are usually negative. A positive family history of asthma is less common. Respiratory in- fections due to viruses (e.g., rhinovirus, parainfluenza virus) and inhaled air pollutants (e.g., sulfur dioxide, ozone, nitrogen dioxide) are common triggers. Also important are other environmental triggers, such as cold air, stress, and exercise. It is thought that virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants. Although the connections are not well understood, the ultimate humoral and cellular mediators of airway obstruction (e.g., eosinophils) are common to both atopic and nonatopic variants of asthma, so treatment is similar. Drug-Induced Asthma Several pharmacologic agents provoke asthma, aspirin being the most striking example. Patients with aspirin sensitivity present with recur- rent rhinitis, nasal polyps, urticaria, and bronchospasm. The precise FIG. 11.11 Bronchial biopsy specimen from an asthmatic patient pathogenesis is unknown but is likely to involve some abnormality in showing subbasement membrane fibrosis, eosinophilic inflammation, prostaglandin metabolism stemming from inhibition of cyclo- and smooth muscle hyperplasia. oxygenase by aspirin. Patients with relatively mild episodic disease are usually treated Occupational Asthma symptomatically with bronchodilators (such as beta-agonist drugs) Occupational asthma may be triggered by fumes (e.g., epoxy resins, and glucocorticoids, sometimes in combination with leukotriene in- plastics), organic and chemical dusts (e.g., wood, cotton, platinum), hibitors (recall that leukotrienes are potent bronchoconstrictors). In gases (e.g., toluene), and other chemicals. Asthma attacks usually patients with more severe disease who have elevated eosinophil counts, develop after repeated exposure to the inciting antigen(s). high IgE levels, and other evidence of a heightened Th2 response, antibodies that block the action of specific immune mediators (such as MORPHOLOGY IL-4, IL-5, and IgE) are beneficial. The morphologic changes in asthma have been described in individuals who Bronchiectasis die due to severe attacks and in mucosal biopsy specimens of individuals Bronchiectasis is the permanent dilation of bronchi and bronchi- challenged with allergens. In fatal cases, the lungs are distended due to air oles caused by destruction of smooth muscle and supporting elastic trapping (overinflation), and there may be small areas of atelectasis. The most tissue; it typically results from or is associated with chronic striking finding is occlusion of bronchi and bronchioles by thick, tenacious necrotizing infections. It is not a primary disorder, as it always occurs mucous plugs containing whorls of shed epithelium (Curschmann secondary to persistent infection or obstruction caused by a variety of spirals). Numerous eosinophils and Charcot-Leyden crystals (see conditions. Bronchiectasis gives rise to a characteristic symptom eFig. 11.3) are also present. Other characteristic morphologic changes in complex dominated by cough and expectoration of copious amounts asthma (Fig. 11.10B), collectively called airway remodeling, include of purulent sputum. Diagnosis depends on an appropriate history and Thickening of airway wall radiographic demonstration of bronchial dilation. The conditions that Subbasement membrane fibrosis (Fig. 11.11) most commonly predispose to bronchiectasis include: Increased submucosal vascularity Bronchial obstruction. Common causes are tumors, foreign bodies, An increase in size of the submucosal glands and goblet cell metaplasia of and impaction of mucus. In these conditions, bronchiectasis is the airway epithelium localized to the obstructed lung segment. Bronchiectasis may also Hypertrophy and/or hyperplasia of bronchial muscle complicate atopic asthma and chronic bronchitis. Congenital or hereditary conditions, for example: Cystic fibrosis, in which widespread severe bronchiectasis results Clinical Features. An attack of asthma is characterized by severe from obstruction caused by abnormally viscid mucus and sec- dyspnea and wheezing due to bronchoconstriction and mucus plug- ondary infections (Chapter 4) ging, which leads to trapping of air in distal air spaces and progressive Immunodeficiency states, particularly immunoglobulin defi- hyperinflation of the lungs. In the usual case, attacks last from 1 to ciencies, in which localized or diffuse bronchiectasis develops several hours and subside either spontaneously or with therapy. In- because of recurrent bacterial infections tervals between attacks are characteristically free from overt respira- Primary ciliary dyskinesia (also called immotile cilia syndrome), tory difficulties, but persistent subtle deficits can be detected by a rare autosomal recessive disorder that is frequently associated pulmonary function tests. Occasionally a severe paroxysm occurs that with bronchiectasis and sterility in males. It is caused by does not respond to therapy and persists for days and even weeks inherited abnormalities of cilia, thereby impairing mucociliary (status asthmaticus). The associated hypercapnia, acidosis, and severe clearance of the airways, leading to persistent infections hypoxia may be fatal, although in most cases the condition is more Necrotizing, or suppurative, pneumonia, particularly with virulent disabling than lethal. organisms such as Staphylococcus aureus or Klebsiella spp., 410 CHAPTER 11 Lung predisposes affected patients to development of bronchiectasis. cultures reveal mixed flora; the usual organisms include staphylococci, Post-tuberculosis bronchiectasis continues to be a significant cause streptococci, pneumococci, enteric organisms, anaerobic and microaerophilic of morbidity in endemic areas. Advanced bronchiectasis has also bacteria, and (particularly in children) Haemophilus influenzae and Pseudo- been reported after SARS-CoV-2 pneumonia. monas aeruginosa. When healing occurs, the lining epithelium may regenerate completely; Pathogenesis. Two intertwined processes contribute to bronchiec- however, the injury usually cannot be repaired, and abnormal dilation and tasis: obstruction and chronic infection. Either may be the initiator. scarring persist. Fibrosis of the bronchial and bronchiolar walls and peri- For example, obstruction caused by a foreign body may impair bronchiolar fibrosis develop in more chronic cases. In some instances, the clearance of secretions, providing a favorable substrate for super- necrosis destroys the bronchial or bronchiolar walls, producing an abscess imposed infection. The resultant inflammatory damage to the bron- cavity. chial wall and the accumulating exudate further distend the airways, leading to irreversible dilation. Conversely, a persistent necrotizing infection in the bronchi or bronchioles may lead to poor clearance of secretions, obstruction, and inflammation with peribronchial fibrosis Clinical Features. Bronchiectasis is characterized by severe, persis- and traction on the bronchi, culminating again in full-blown tent cough associated with expectoration of mucopurulent, some- bronchiectasis. times foul-smelling, sputum. Other common symptoms include dyspnea, rhinosinusitis, and hemoptysis. Symptoms are often episodic MORPHOLOGY and are precipitated by upper respiratory tract infections or the Bronchiectasis usually affects the lower lobes bilaterally, particularly the most introduction of new pathogenic agents. Severe widespread bronchi- vertical air passages. When caused by tumors or aspiration of foreign bodies, ectasis may lead to significant obstructive ventilatory defects, with it may be sharply localized to a single segment of the lungs. Usually, the most hypoxemia, hypercapnia, pulmonary hypertension, and cor pulmo- severe involvement is found in the more distal bronchi and bronchioles. The nale. However, with current treatment, outcomes have improved and airways may be dilated to as much as four times their usual diameter and severe complications of bronchiectasis, such as brain abscess, can be seen on gross examination almost to the pleural surface (Fig. 11.12). By amyloidosis (Chapter 5), and cor pulmonale, occur less frequently now contrast, in healthy lungs, the bronchioles cannot be followed by eye beyond a than in the past. Resection of the affected part of lung is needed in point 2 to 3 cm from the pleura. some cases. The histologic findings vary with the activity and chronicity of the disease. In severe active cases, an intense acute and chronic inflammatory exudate within the walls of the bronchi and bronchioles leads to desquamation of CHRONIC INTERSTITIAL (RESTRICTIVE, INFILTRATIVE) lining epithelium and extensive areas of ulceration. Typically, sputum LUNG DISEASES Chronic interstitial lung diseases are a heterogeneous group of disorders characterized by bilateral, often patchy, pulmonary fibrosis mainly affecting the walls of alveoli. Many of the entities in this group are of unknown cause and pathogenesis; some have both an intraalveolar and an interstitial component. Chronic interstitial lung diseases are categorized based on clinicopathologic and histo- logic features (Table 11.2), but the histologic features among the various entities often overlap. The similarity in clinical signs, symp- toms, radiographic findings, and pathophysiologic and histologic Table 11.2 Major Categories of Chronic Interstitial Lung Disease Fibrosing Idiopathic pulmonary fibrosis/usual interstitial pneumonia Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Collagen vascular disease-associated Pneumoconiosis Therapy-associated (drugs, radiation) Granulomatous Sarcoidosis Hypersensitivity pneumonia Eosinophilic Loeffler syndrome Drug allergyeassociated Idiopathic chronic eosinophilic pneumonia FIG. 11.12 Bronchiectasis in a patient with cystic fibrosis who under- Smoking-Related went lung resection for transplantation. Cut surface of lung shows Desquamative interstitial pneumonia markedly dilated bronchi filled with purulent mucus that extend to sub- Respiratory bronchiolitis pleural regions.  CHAPTER 11 Lung 411 changes justify their consideration as a group. The shared hallmark of the interlobular septa. The earliest lesions demonstrate exuberant fibroblastic these disorders is reduced lung compliance (stiff lungs), which in turn proliferation (fibroblastic foci) (Fig. 11.15). Over time these areas become necessitates increased effort to breathe (dyspnea). Furthermore, more collagenous and less cellular. A typical finding is the coexistence of both damage to the alveolar epithelium and interstitial vasculature pro- early and late lesions. The dense fibrosis causes collapse of alveolar walls duces abnormalities in the ventilation-perfusion ratio, leading to and formation of cystic spaces (honeycomb fibrosis) lined by hyper- hypoxia. Chest radiographs show small nodules, irregular lines, or plastic type II pneumocytes or bronchiolar epithelium. The interstitial “ground-glass shadows.” With progression, patients may develop inflammation consists of alveolar septal infiltrates of lymphocytes and occa- respiratory failure, pulmonary hypertension, and cor pulmonale sional plasma cells, mast cells, and eosinophils. Secondary pulmonary hy- (Chapter 9). When advanced, the etiology of the underlying diseases pertensive changes (intimal fibrosis and medial thickening of pulmonary may be difficult to determine because all these disorders result in arteries) are often present. diffuse scarring and gross destruction of the lung, referred to as end- stage or “honeycomb” lung. Clinical Features. IPF usually presents with the gradual onset of a Fibrosing Diseases nonproductive cough and progressive dyspnea. On physical exami- Idiopathic Pulmonary Fibrosis (Usual Interstitial Pneumonia) nation, most patients have characteristic “dry” or “velcro-like” Idiopathic pulmonary fibrosis (IPF) refers to a pulmonary disorder crackles during inspiration. Cyanosis, cor pulmonale, and peripheral of unknown etiology that is characterized by patchy, progressive edema may develop in later stages of the disease. The characteristic bilateral interstitial fibrosis. The radiologic and histologic pattern of clinical and radiologic findings (i.e., subpleural and basilar fibrosis, fibrosis is referred to as usual interstitial pneumonia (UIP), which is reticular abnormalities, and “honeycombing”) are often diagnostic required for the diagnosis of IPF. Because its etiology is unknown, it is also known as cryptogenic organizing alveolitis. Males are affected more often than females, and it is a disease of older adults, virtually never occurring before 50 years of age. Of note, similar pathologic ENVIRONMENTAL FACTORS changes in the lung may be present in entities such as asbestosis, Smoking collagen vascular diseases, and other conditions, and IPF is therefore Occupational a diagnosis of exclusion. exposure Gastroesophageal Pathogenesis. The interstitial fibrosis that characterizes IPF is reflux believed to result from repeated injury and defective repair of Other irritants and toxins alveolar epithelium, often in a genetically predisposed individual Viral infections (Fig. 11.13). The cause of the injury is obscure; a variety of sources have been proposed, including chronic gastroesophageal reflux. However, only a small fraction of individuals with reflux or who have Aging been exposed to other proposed environmental triggers develop IPF; Genetic risk factors: thus, other unknown factors must have an important role. The clearest etiologic clues come from genetic studies. Germline muta- Telomerase mutations tions leading to loss of telomerase function are associated with Surfactant mutations increased risk, suggesting that cellular senescence contributes to a MUC5B variant profibrotic phenotype. Approximately 35% of affected individuals have a genetic variant in the MUC5B gene that alters the production of mucin, while a smaller number of affected patients have germline mutations in surfactant genes. These genes are only expressed in lung At risk epithelium Persistent epithelial epithelial cells, suggesting that epithelial cell abnormalities are key injury/activation initiators of IPF. It is hypothesized that abnormal epithelial repair at the sites of chronic injury and inflammation gives rise to exuberant fibroblastic or myofibroblastic proliferation and collagen deposition. Innate and adaptive Profibrogenic factors immune responses Although the mechanisms of fibrosis are incompletely understood, excessive activation of profibrotic factors such as TGF-b is likely to be involved. One school of thought holds that alveolar macrophages with an M2 phenotype (Chapter 2) have a central role in driving Pathogenic activation of signaling pathways fibrosis due to their ability to secrete cytokines that promote fibro- blast activation. MORPHOLOGY Fibroblastic proliferation, collagen production Grossly, the pleural surfaces of the lung are cobblestoned due to retraction of scars along the interlobular septa. The cut surface shows firm, rubbery, white areas of fibrosis. Histologically, the hallmark is patchy interstitial FIBROSIS fibrosis, which varies in amount (Fig. 11.14) and worsens with time. It occurs preferentially within the lower lobe, the subpleural regions, and along FIG. 11.13 Proposed pathogenic mechanisms in idiopathic pulmonary fibrosis. MUC5B, Mucin 5B. See text for details. 412 CHAPTER 11 Lung Cryptogenic organizing pneumonia is a second uncommon entity associated with fibrosis. It presents with cough and dyspnea, and chest radiographs show subpleural or peribronchial patchy areas of airspace consolidation consisting of intraalveolar plugs of loose organizing connective tissue. Some patients recover spontaneously, while most require treatment, usually with oral steroids. The differential diagnosis of fibrosing pulmonary disorders also in- cludes autoimmune disorders such as systemic sclerosis, rheuma- toid arthritis, and systemic lupus erythematosus, all of which may be complicated by diffuse pulmonary fibrosis. Pneumoconioses Pneumoconiosis is a term originally coined to describe lung disorders caused by inhalation of mineral dusts. The term has since been broadened to include diseases induced by organic and inorganic FIG. 11.14 Usual interstitial pneumonia. The fibrosis, which varies in particulates, and some experts also regard chemical fume- and vapor- intensity, is more pronounced in the subpleural region. induced lung diseases as pneumoconioses. The mineral dust pneumoconiosesdmost commonly caused by inhalation of coal dust, silica, and asbestosdusually stem from exposure in the workplace. In (eFig. 11.4). Antiinflammatory therapies have proven to be of little the case of asbestos, an increased risk for cancer extends to the family use, in line with the idea that inflammation is of secondary members of asbestos workers and to individuals exposed outside of the pathogenic importance. By contrast, antifibrotic therapies such as workplace. nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an inhibitor of TGF-b, are now approved for use. The overall Pathogenesis. The reaction of the lung to mineral dusts depends on prognosis remains poor, however; survival is only 3 to 5 years, and the size, shape, and solubility of the particles and their inherent pro- lung transplantation is the only definitive treatment. inflammatory properties. For example, particles greater than 5 to 10 mm are unlikely to reach distal airways, and particles smaller Other Fibrosing Diseases than 0.5 mm move into and out of alveoli, often without significant Other rare pulmonary diseases associated with fibrosis must be deposition and injury. Particles that are 1 to 5 mm in diameter are considered in the differential diagnosis of IPF, several of which are of greatest concern as they tend to lodge at the bifurcation of the worthy of brief mention (see Table 11.2). distal airways. Coal dust is relatively inert, and large amounts must Nonspecific interstitial pneumonia (NSIP) is a chronic bilateral be deposited in the lungs before lung disease is clinically interstitial lung disease of unknown etiology, which (despite its detectable. Silica, asbestos, and beryllium stimulate greater immune name) has distinct radiologic, histologic, and clinical features, response than coal dust, resulting in fibrotic reactions at lower including a frequent association with collagen vascular disorders concentrations. such as rheumatoid arthritis. NSIP is important to recognize The pulmonary alveolar macrophage is a key cellular element in because it has a much better prognosis than IPF. It is characterized the initiation and perpetuation of inflammation, lung injury, and by mild to moderate interstitial chronic inflammation and/or fibrosis. Following phagocytosis by macrophages, many particles fibrosis that is patchy but uniform in the areas involved. activate the inflammasome and induce production of the pro- inflammatory cytokine IL-1 as well as the release of other factors. These factors initiate an inflammatory response that leads to fibroblast proliferation and collagen deposition. Some of the inhaled particles may reach the lymphatics either by direct drainage or within migrating macrophages and thereby initiate an immune response to components of the particulates and/or to self proteins that are modified by the particles. This leads to an amplification and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than other particles. Coal Workers’ Pneumoconiosis Dust reduction in coal mines has greatly reduced the incidence of coal dusteinduced disease; however, there is an increasing prevalence of coal workers’ pneumoconiosis (CWP) in older miners in the United States, particularly in the region known as Appalachia. The spectrum of lung findings in coal workers is wide, ranging from asymptomatic anthracosis, in which carbon pigment deposits without a perceptible cellular reaction; to simple CWP, in which macrophages accumulate with little to no pulmonary dysfunction; to complicated CWP or FIG. 11.15 Usual interstitial pneumonia. Fibroblastic focus with fibers progressive massive fibrosis (PMF), in which fibrosis is extensive and running parallel to surface and bluish myxoid extracellular matrix. Hon- lung function is compromised (see Table 11.3). Although statistics eycombing is present to the left. vary, it seems that less than 10% of cases of simple CWP progress to  CHAPTER 11 Lung 412.e1 eFIG. 11.4 Idiopathic pulmonary fibrosis, CT scan. Bilateral increased interstitial markings are seen as well as clear spaces (honeycomb lung). (From Klatt EC: Robbins and Cotran Atlas of Pathology, ed 4, Fig. 5.38, Philadelphia, 2021, Elsevier.)  CHAPTER 11 Lung 413 PMF. Of note, PMF is a generic term that is applied to confluent Clinical Features. CWP is usually a benign disease that produces little pulmonary fibrosis; it may arise in any of the pneumoconioses dis- decline in lung function. In those in whom PMF develops, there is cussed here. increasing pulmonary dysfunction, pulmonary hypertension, and cor Although coal is mainly carbon, coal mine dust contains a variety pulmonale. Progression from CWP to PMF has been linked to of trace metals, inorganic minerals, and crystalline silica. In general, exposure to higher coal dust levels and to total dust burden. Once the risk of CWP is higher in miners working in areas in which coal has established, PMF tends to progress even in the absence of further higher levels of contaminating chemicals and minerals. exposure. After taking smoking-related risk into account, there is no increased frequency of lung carcinoma in coal miners, a feature that MORPHOLOGY distinguishes CWP from both silica and asbestos exposures Pulmonary anthracosis is the most innocuous coal-induced pulmo- (discussed next). nary lesion in coal miners and is also commonly seen in urban dwellers and Silicosis individuals who smoke tobacco. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in the con- Silicosis is currently the most prevalent chronic occupational dis- nective tissue along the pulmonary and pleural lymphatics and in draining ease in the world. It is caused by inhalation of crystalline silica, mostly lymph nodes. in occupational settings. Workers involved in sandblasting and hard- Simple CWP is characterized by the presence of coal macules and rock mining are at particularly high risk. Silica occurs in both crys- larger coal nodules. The coal macule consists of dust-laden macrophages talline and amorphous forms, but crystalline forms (including quartz, and small amounts of collagen fibers arrayed in a delicate network. Although cristobalite, and tridymite) are by far the most toxic and fibrogenic. Of these lesions are scattered throughout the lung, the upper lobes and upper these, quartz is most commonly implicated in silicosis. After inhala- zones of the lower lobes are more heavily involved. In due course, cen- tion, silica particles are ingested by alveolar macrophages, leading to trilobular emphysema may occur. lysosomal damage, activation of the inflammasome, and release of Complicated CWP (PMF) occurs on a background of simple CWP by inflammatory mediators, including IL-1, TNF, lipid mediators, coalescence of coal nodules and generally develops over many years. It is oxygen-derived free radicals, and fibrogenic cytokines. characterized by multiple, dark black scars larger than 2 cm and sometimes up to 10 cm in diameter that consist of dense collagen and pigment (Fig. 11.16). MORPHOLOGY Silicotic nodules in their early stages are tiny, barely palpable, discrete, pale-to-black (if coal dust is present) nodules in the upper zones of the lungs (Fig. 11.17). Microscopically, silicotic nodules have concentrically ar- ranged hyalinized collagen fibers surrounding an amorphous center. The “whorled” appearance of the collagen fibers is quite characteristic (Fig. 11.18). Examination of the nodules by polarized microscopy re- veals weakly birefringent silica particles, primarily in the center of the nodules. As the disease progresses, individual nodules may coalesce into hard, collagenous scars, with eventual progression to PMF. The intervening lung parenchyma may be compressed or overexpanded, and a honeycomb pattern may develop. Fibrotic lesions may also occur in hilar lymph nodes and the pleura. Clinical Features. Silicosis is usually detected i