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Page 1 Bronchiolar
Airway Disorders and Bronchiolitis Obliterans
Bronchiolar lesions continue to be an important cause of airflow obstruction. Major historical milestones of the bronchiolar diseases began when Lange described two patients in 1901 (1). Then fume and infectious causes were described. Eventually bronchiolar lesions were described in the connective tissue disorders, post bone marrow transplantation and lung transplantation, Table 1. The bronchiolar interstitial disorder BOOP is discussed in this Web site. Bronchiolar anatomy Bronchioles are small airways, one to two millimeters or less in diameter, without cartilage or submucosal glands, Table 2. There are about 30,000 terminal bronchioles, which represent the final conducting bronchioles at the 11 to 16th generation, with diameters of about 0.6 millimeters (2). Terminal bronchioles typically branch into two or three respiratory bronchioles. They are distinctive because alveolar sacs are seen in their walls. There are about 224,000 respiratory bronchioles and usually about three generations, one to two alveoli in the proximal respiratory bronchioles and several in the most distal. These terminate at the 13.8 million alveolar ducts and 300 million alveoli. Bronchiolar functional anatomy Histologically, the distal bronchioles have connective tissue and smooth muscle in the airway walls but do not have submucosal glands or cartilage. The epithelium of the terminal bronchioles is composed of three types of cells - ciliated cells, nonciliated cells and a few basal cells. The epithelium of the respiratory bronchioles has three cell populations. The first near the terminal bronchioles consists of the nonciliated columnar, ciliated columnar and basal cells. The second consists of nonciliated cuboidal cells. The third is most similar to the alveolar epithelial lining. These are nonciliated cells, cuboidal type II cells, and squamous type I cells. The non-ciliated columnar cells of the terminal bronchioles, and the non-ciliated cuboidal and columnar cells of the respiratory bronchioles are involved in the biosynthesis and release of secretory products into the airway lumina (2). The distribution of cell types varies along the airways (3). Ciliated cells predominate on the surface of the epithelium of the proximal airways while Clara cells compose the majority of cells in the bronchiolar mucosa. These cells are columnar with apical surfaces bulging into the airway lumen. Apically, Clara cells contain membrane-bound secretory granules probably active in the secretion of proteins. The Clara cell may also be active in surfactant secretion. Neuroendocrine cells reach maximal density in the proximal bronchioles, and are rarely found in the terminal bronchioles. They occur singly and in clusters and tend to be concentrated at the bifurcations of the conducting airways (3). Neuroendocrine cell hyperplasia (4) may occur in patients with peripheral carcinoid tumor, and nearly one-half of these patients may have obliterative bronchiolitis, some with airflow obstruction (5). In these patients, subepithelial fibrosis varies in severity. In the most severe lesions, the lumen may be replaced by fibrous tissue with few remaining neuroendocrine cells. These investigators suggested that neuroendocrine hyperplasia preceded and presumably caused the airway fibrosis. PATHOLOGICAL CLASSIFICATION Cellular bronchiolitis is an acute or chronic inflammation of the bronchioles. The inflammation may be submucosal, mural or peribronchiolar (6). Follicular bronchiolitis is a descriptive term for a subset of cellular bronchiolitis associated with lymphoid hyperplasia and reactive germinal centers along the small airways and bronchioles (6). Mineral dust bronchiolitis is fibrotic thickening of the walls of the terminal and respiratory bronchioles, and in some instances with extension of the process into alveolar ducts (7,8). The lesion has been described in workers exposed to a wide variety of inorganic dusts such as iron oxide, aluminum oxide, asbestos, talc, mica, coal, and silica (8). Cigarette smoke respiratory bronchiolitis has several features (7). The bronchioles are thickened as a result of inflammatory edema and cellular infiltrates. The airway wall is distorted because of fibrous tissue scarring in both the submucosa and adventitial compartments. There is early airway collapse on expiration secondary to destruction of the peribronchiolar alveolar attachments and loss of airways-parenchymal interdependence. Airway reactivity may also occur as a result of this inflammatory process. There are increasing findings that indicate that active events constantly triggered by cigarette smoking can accentuate narrowing and promote a chronic inflammatory process resulting in thick, inflamed, deformed, and narrow airways with emphysematous changes around them (9-10). This uncontrolled inflammatory process in the terminal and respiratory bronchioles may eventually be responsible for centrilobular destruction of the lungs and may be related to T-lymphocytes (11). Diffuse panbronchiolitis is characterized by chronic inflammation of respiratory bronchioles with interstitial accumulation of foam cells in the walls of respiratory bronchioles, adjacent alveolar ducts, and alveoli (12). Constrictive bronchiolitis is a late, fibrotic, concentric bronchiolitis with or without complete obliteration, Table 3 (6,13). This is a lesion of the bronchioles without primary involvement of the distal alveolar ducts and alveoli. The histologic changes associated with constrictive bronchiolitis vary from mild bronchiolar inflammation and scarring to concentric fibrosis with complete obliteration of the bronchioles. Bronchiolitis obliterans with intraluminal polyps is a nonspecific reaction to bronchiolar injury that is characterized by an organizing intraluminal exudate with proliferative granulation tissue polyps filling the lumens of terminal and respiratory bronchioles (13) and sometimes referred to as proliferative bronchiolitis obliterans. This reaction usually extends in a continuous fashion into alveolar ducts and sometimes into distal alveoli representing an organizing pneumonia (6,13, 14, 15). Conditions associated with this lesion include organizing diffuse alveolar damage (organizing ARDS), organizing infections, distal to obstruction, organizing aspiration pneumonia, organizing phase of toxic fume exposure, connective tissue disorders, hypersensitivity pneumonitis, organizing eosinophilic pneumonia, drug reactions, bone marrow, heart-lung and lung transplantation, diffuse panbronchiolitis and BOOP (13). Respiratory bronchiolitis-interstitial lung disease occurs among smokers and is characterized by a mononuclear inflammatory process involving the submucosa of the distal and respiratory bronchioles and associated with fibrous scarring that extends into surrounding alveolar walls. The findings are dominated by tan-brown pigmented macrophages within respiratory bronchioles as well as neighboring alveolar ducts and alveoli (16).
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