Loss of normal type I alveolar epithelium and replacement by hyperplastic type II cells or bronchiolar cuboidal cells is a consistent finding in patients with IPF.
In addition to altered mesenchymal cells, abnormalities of the alveolar epithelium in patients with pulmonary fibrosis have been noted from the earliest descriptions of the disease process. Independent of the source of fibroblast expansion in the lungs (resident or systemic), it seems agreed upon that the ultimate effector cell in pulmonary fibrosis is the myofibroblast, a differentiated fibroblast which has contractile properties similar to smooth muscle cells, and which is characterized by the presence of alpha-smooth muscle actin (α-SMA). Several possible origins of ECM-producing mesenchymal cells have been described, and have included accumulation of resident lung fibroblasts, homing and fibroblastic differentiation of bone marrow-derived cells such as circulating fibrocytes or monocytes, or epithelial-mesenchymal transition (EMT).
When the balance between fibroblast proliferation and apoptosis is shifted toward accelerated proliferation or slowed apoptosis, fibroblasts - the primary ECM producers - accumulate. When the normal balance between ECM deposition and turnover is shifted toward deposition or away from breakdown, excessive ECM accumulates. The pathologic findings in pulmonary fibrosis (excessive accumulation of ECM and remodeling of the lung architecture) are a consequence of disturbances in two physiologically balanced processes: proliferation and apoptosis of fibroblasts, and accumulation and breakdown of ECM. Currently, IPF is considered the most common and severe form of pulmonary fibrosis, with a disheartening median survival of approximately three years, with no proven effective therapy, and with lung transplantation remaining the only viable intervention in end-stage disease. With further pathologic analysis, several distinct types of pulmonary fibrosis were described, and the terms diffuse fibrosing alveolitis, diffuse interstitial fibrosis, and idiopathic pulmonary fibrosis (IPF) were introduced to describe a more insidious, yet still debilitating form of chronic pulmonary fibrosis. Although the prognosis of patients with diffuse pulmonary fibrosis is poor, it was subsequently realized that many patients did not have the extremely rapid deteriorating course that was described by Hamman and Rich. Though some descriptions of fibrous diseases of the lungs can be found as early as the 5th century BC by Hippocrates, more modern descriptions of pulmonary fibrosis occurred in the early part of the 20th century with reports by Hamman and Rich of four patients with rapidly progressive diffuse interstitial fibrosis of the lungs. Pulmonary fibrosis is a chronic lung disease characterized pathologically by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture, and additionally characterized by recognizable clinical, physiologic, and radiographic findings. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease.
In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture.
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