Escape from the matrix: multiple mechanisms for fibroblast activation in pulmonary fibrosis

Abstract

Lung fibrosis is a recognized feature of many chronic lung diseases and is central to the pathogenesis of idiopathic pulmonary fibrosis, a disease that carries a prognosis worse than many cancers. Current research into this condition is defining the key pathways of activation either in resident fibroblasts, matrix-producing cells derived from circulating fibrocytes, or epithelial cells that appear to transdifferentiate to fibroblast-like cells. The downstream signaling pathways are also being delineated as well as the gene interactions leading to altered cell phenotype. These studies have led to an appreciation that multiple pathways, including inflammatory and coagulation cascades, are involved in the pathogenesis of idiopathic pulmonary fibrosis. As these facts come to light, we are exploring promising new approaches to treat fibroses and halt the inexorable progression that is a feature of these disorders. This article reviews these findings and our current concepts of the key molecular events leading to tissue damage and excessive matrix deposition in lung fibrosis. It also highlights the need for new studies to delineate alternative pathogenetic mechanisms and integrate these pathways so we have a framework to better understand their importance in individual patients.

Figure 1.

Fibroblasts and factors. CGRP = calcitonin gene-related peptide; ECP = eosinophil chemotactic protein; EGF = epidermal growth factor; ET-1 = endothelin-1; FGF2 = fibroblast growth factor 2; GM-CSF = granulocyte-macrophage colony–stimulating factor; IGF-1 = Insulin-like growth factor-1; LTB4 = leukotriene B4; MCP-1 = monocyte chemotactic protein-1; PAF = platelet activating factor; PDGF = platelet-derived growth factor; PGD2 = prostaglandin D2; PGE2 = prostaglandin E2; PGF2α = prostaglandin F2α; PGI2 = prostacyclin; TGF-α = transforming growth factor-α; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α. Reprinted by permission from Reference .

Figure 2.

Sources of fibroblasts and myofibroblasts in pulmonary fibrosis. Blood-borne fibrocytes, derived from bone marrow stem cells, target to the lung where they may play roles in elaborating matrix. Fibroblasts may also be derived from the transdifferentiation of epithelial cells, a process termed epithelial–mesenchymal transition (EMT). Finally, resident fibroblasts are also capable of transdifferentiation into myofibroblasts, which exhibit both a contractile and matrix-producing phenotype. The relative importance of these pathways in human disease is yet to be elucidated. ECM = extracellular matrix. Adapted by permission from Reference .