| Angiogenesis, apoptosis and re-epithelialization at the foci of recent injury in usual interstitial pneumonia and bronchiolitis obliterans organizing pneumonia | ||
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The lung is a unique internal organ exposing itself directly and constantly to the surrounding atmosphere. The main function of the lung is gas exchange, but it also performs many non-respiratory functions. For example, the lung detoxifies inhaled or ingested noxious agents, controls air and vascular flows, produces surfactant, and participates in transportation, degradation and production of diverse biologically active substances. The gross structural arrangement of the lung is analogous to that of a tree; the trachea is the trunk, the bronchi are its branches, and the alveoli its leaves. The trachea and bronchi provide the rigid conducting system, and the major function of gas exchange occurs in the alveoli. The lung has dual blood supplies. The pulmonary arterial circulatory system arises from the right ventricle of the heart, follows the bronchi and bronchioles, and accommodates total systemic venous return. The bronchial arterial circulatory system is a part of the systemic circulation, and nourishes the bronchial tree as far as the respiratory bronchioles. Because of its sturdiness and efficiency, vigilant defense mechanisms, and enormous reserve capacities, the lung frequently becomes irreversibly damaged before the person becomes symptomatic (Dail & Hammar 1994).
Normal alveoli are lined by flattened type I pneumocytes and cuboidal type II pneumocytes, both of which form tight junctions (Wolff & Crystal 1997). Type II pneumocytes are more numerous than type I pneumocytes, but they cover only 7 % of alveolar surface, while the attenuated type I cells cover the remaining 93 % (Crapo et al. 1982). Gas transfer takes place across the alveolar-capillary membrane, which consists of attenuated cytoplasm of type I pneumocyte, the endothelial cell cytoplasm and their irregularly fused basement membranes (BMs). The two constituent cell layers also form the air-blood barrier that keeps the lung “dry” and maintains complete separation of three fluid media: blood plasma, interstitial fluid, and alveolar lining layer (Schneeberger 1997, Simionescu 1997). The functions of type II cells include synthesis and secretion of surface-active material, maintenance of alveolar epithelium by proliferating and differentiating into type I cells, maintenance of minimal amount of alveolar fluid by sodium transport, and secretion of a variety of growth factors and cytokines, such as transforming growth factor-beta (TGF-β ), TGFα, interleukin-8 (IL-8), IL-6, monocyte chemoattractant protein (MCP-1), tumor necrosis factor-alpha (TNF-α), granulocyte macrophage-colony stimulating factor (GM-CSF), endothelin-1 (ET-1), and nitric oxide (Mason & Shannon 1997).
The normal alveolar epithelial and endothelial BMs are thin and continuous, except for localized interruptions under type II cells. The role of BMs is to create structural support and molecular barrier, to induce some cellular functions including cell adhesion and migration and to mediate survival signals for adjacent cells. Type IV collagens, laminins, entactin/nidogen, and heparan sulfate proteoglycan perlecan are the principal components of BMs (Crouch et al. 1997). Anchoring fibers containing type VII collagen have been occasionally identified in fibrotic human lung as a minor component of BMs (Kawanami et al. 1982).
Capillary endothelial cells make up 30% of the cells in the alveolar region of the lung and they comprise 14% of the alveolar tissue volume (Crapo et al. 1982). The endothelium of the alveolar capillaries of the normal lung forms a continuous surface lining the endothelial BM. Endothelial cells are joined to one another by tight junctions, and their permeability properties and resistance to injury are essential for the preservation of the air-blood barrier (Simionescu 1997). Endothelial cells are metabolically active, participating in molecular transport, degradation, and production (Silverman et al. 1997).
The role of the interstitium is to separate and bind together the cell layers of the airspace epithelium and the vascular endothelium, and to join different parts of the lung (Weibel & Crystal 1997). Moreover, ordered layering of different cell types and BM maintains normal communication between cells and extracellular matrix (ECM) components. The ECM is a highly specialized, controlled and dynamic complex of macromolecules that lies underneath epithelial cells and surrounds connective tissue cells. In addition to its supportive property it directs many functional processes e.g. signaling, tissue differentiation, adhesion, regeneration and migration (Adams & Watt 1993). In normal lung, the major constituents of the extracellular matrix include collagen types I, III, V and VI, elastic fibers, fibronectin, proteoglycans, and BM proteins. Mesenchymal cells are mainly fibroblasts, myofibroblasts, and pericytes. Undifferentiated mesenchymal cells and smooth muscle cells are relatively uncommon. The inflammatory cells include T and B lymphocytes and natural killer cells, mast cells, as well as rare polymorphonuclear leukocytes and mononuclear phagocytes (Weibel & Crystal 1997).