A matrix for new ideas in pulmonary fibrosis.

Abstract

Pulmonary fibrosis is a progressive and ultimately fatal condition, characterized pathologically by mesenchymal cell proliferation in the lung, expansion of the extracellular matrix (ECM), and extensive remodeling of the lung parenchyma. Although the pathogenesis of this disease is complex and poorly understood, growth factors, cytokines, chemokines, and regulators of apoptosis have all been implicated in its progression. Pulmonary fibrosis has been traditionally viewed as a consequence of inflammation, but this interpretation has been questioned in recent years because clinical measures of inflammation do not correlate well with disease progression and because anti-inflammatory drugs do not significantly affect clinical outcome. For these reasons, recent attention has focused on the ECM and molecules that normally regulate its homeostasis. Among the molecules thought to regulate matrix deposition, transforming growth factor (TGF)- � 1 is probably the best-studied. This fibrogenic growth factor is upregulated in lung parenchyma from patients with idiopathic pulmonary fibrosis (1), it increases the production of collagen and other extracellular matrix components (2‐4), and it regulates the expression of other genes associated with ECM degradation and proteolysis. Moreover, adenoviral delivery of active TGF- � 1 to rat lung results in architectural changes similar to those seen in pulmonary fibrosis (5). Other studies have revealed that overexpression of granulocyte macrophage‐colony stimulating factor (2), tumor necrosis factor- � (3), and interleukin-13 (4) also result in myofibroblast proliferation and ECM deposition. Interestingly, a common feature among these latter studies is the upregulation of TGF- � 1 expression in the lung, further supporting the hypothesis that this cytokine plays an important role in pulmonary fibrosis. Additional evidence for the importance of TGF- � 1 in pulmonary fibrosis is provided by the observation that TGF- � 1 may play a role in susceptibility to fibrogenic agents in mice. For example, expression of TGF- � 1 in the