ABSTRACT
The pathogenesis of fibrotic diseases is similar regardless of whether the lung or extrapulmonary tissues are involved. The disease is characterized by chronic inflammation, excessive accumulation of matrix proteins and destruction of normal tissue structure.1,2
Although the etiology of pulmonary fibrotic diseases is diverse, the process universally involves an imbalance between matrix formation and degradation. Studies have shown that accumulation of matrix proteins, mainly produced by fibroblasts and myofibroblasts, is responsible for the alveolar wall damage and distortion of lung parenchyma. Three, sometimes overlapping, phases have been proposed in the development of pulmonary fibrosis including initial triggering events, the inflammatory response and the fibrotic response. A diverse group of insults including drugs (bleomycin, cisplatin), radiation, physical injury, or viral infections as well as collagen-vascular diseases, such as systemic sclerosis, may trigger the development of fibrosis.1,3 Regarding environmental factors, an elevated risk for idiopathic pulmonary fibrosis (IPF) occurs in subjects exposed to mineral dusts (e.g. silica or asbestos), metal or wood dust and tobacco smoking.4-6
The tissue response involves sequentially alveolar epithelial cell injury or activation, inflammation, proliferation, and differentiation of interstitial cells and collagen production. Chronic inflammation occurs following the initial injury and is characterized by activation of resident cells and inflammatory cell infiltration, interstitial edema and local cell proliferation.1,7 Cytokines, such as interleukin-1 (IL)-1, IL-4, IL-8 and tumor necrosis factor (TNF)-a, and growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-b1, are involved in the recruitment of inflammatory cells into the alveolar walls and spaces. A number of these mediators also play a role in the remodeling process through fibroblast proliferation and collagen synthesis. Therefore, the early and persistent expression of pro-inflammatory cytokines and subsequent presence of cell-surface adhesion molecules and chemotactic molecules are important in mediating
fibrosis.2,3 Although this pathway is common for most interstitial lung diseases, IPF may develop in the absence of an inflammatory process.8,9 If inflammation is not resolved, fibroblasts migrate and proliferate in areas of acute injury and secrete an excessive amount of collagen and other matrix proteins. These proteins are deposited in the interstitial space and gradually cause irreversible pulmonary fibrosis.10-12 Fibroblasts also release proteases that degrade and remodel the matrix proteins.2 The aberrant tissue remodeling involves the families of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). The changes in the levels, activities and balance between MMPs and TIMPs play a significant role in the altered extracellular matrix (ECM) metabolism due to their capacity to cleave structural proteins such as collagens and elastin.13,14 Figure 24.1 shows the hypothetical scheme of the events in the pathogenesis of pulmonary fibrosis.
