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Fibrotic lung diseases, typified by idiopathic pulmonary fibrosis (IPF), are essentially untreatable, and new insights into pathogenesis with the potential for therapeutic translation are sorely needed. In the current issue of the Journal (pp. 73-82), Maher and colleagues (1) report a novel role for prostaglandin E^sub 2^ (PGE^sub 2^) that expands on its previously known repertoire of antifibrotic actions. Here we will place into context the important advances in understanding provided by this article alongside our recently reported complementary findings (2).
Research in pulmonary fibrogenesis has prominently centered on the recruitment, proliferation, differentiation, and activation of myofibroblasts, the effector cells of fibrosis responsible for the synthesis, secretion, contraction, and organization of new extracellular matrix. However, it must be remembered that these activities are necessary components of the normal wound repair response to epithelial injury and only become detrimental when they persist inappropriately (3). A fundamental, and critical, distinction between "normal" and "fibrotic" repair therefore lies in the fate of the accumulated myofibroblasts (4). The physiologic resolution of wound repair requires the clearance of myofibroblasts by apoptosis, but a defining feature of IPF is their persistence within fibroblastic foci owing to a striking lack of apoptosis (5). This reflects decreased susceptibility to apoptosis of myofibroblasts from IPF lung when compared with cells from normal lung (5). Normal wound repair additionally requires the successful reestablishment of an intact epithelium, but fibroblastic foci in IPF lung are closely associated with epithelial cells that are undergoing apoptosis (6). Thus, the fibroblastic focus in IPF presents an "apoptosis paradox," in which epithelial and mesenchymal cells within the same microenvironment and (presumably) under the influence of the same soluble mediators demonstrate opposing apoptotic phenotypes (4).
The cellular mechanisms that fuel the apoptosis paradox are incompletely defined. Some mediators known to be increased in IPF, such as transforming growth factor-b1 (TGF-b1) and endothelin-1, protect myofibroblasts from apoptosis through activation of the prosurvival serine-threonine kinase, AKT (7). Others, including angiotensin II and reactive oxygen species along with TGF-b1 itself, promote epithelial cell apoptosis (4). Meanwhile, IPF myofibroblasts secrete decreased levels of hepatocyte growth factor, an epithelial cell mitogen and proapoptotic factor for myofibroblasts (8). Thus, IPF is characterized by an imbalance of mediators that favors myofibroblast survival but epithelial cell apoptosis. The two...