Fibrosis Accumulation in Idiopathic Pulmonary Apoptosis: Implications for Fibroblast Fibroblasts to Fas Ligation-Induced Necessary and Sufficient To Sensitize Lung Increased Cell Surface Fas Expression Is Riches

Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the proinflammatory cytokines TNF-a and IFN-g reverses the resistance of lung fibroblasts to apoptosis. In this study, we investigate the underlying mechanisms. Based on an interrogation of the transcriptomes of unstimulated and TNF-a– and IFN-g–stimulated primary lung fibroblasts and the lung fibroblast cell line MRC5, we show that among Fas-signaling pathway molecules, Fas expression was increased ∼6-fold in an NF-kB– and p38 mapk-dependent fashion. Prevention of the increase in Fas expression using Fas small interfering RNAs blocked the ability of TNF-a and IFN-g to sensitize fibroblasts to Fas ligation-induced apoptosis, whereas enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. Our findings also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant in IPF. P rogressive pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), is thought to arise following injury to, and abnormal repair of, the distal alveolar-capillary units (1). Although little is known about how the alveolar epi-thelium is injured, the ensuing fibrotic response is associated with unrestrained accumulation of fibroblasts and myofibroblasts that synthesize and deposit collagen fibrils within fibroblast foci located in the pulmonary parenchyma (2, 3). Recent studies have suggested that pulmonary fibroblasts arise by several routes including increased migration and proliferation of resident pulmonary fibroblasts, mesenchymal transition of the alveolar epithelium, and recruitment of bone marrow-derived progenitor cells (4–7). In the presence of TGF-b and other agonists, resident fibroblast subsets transdifferentiate into a-smooth muscle actin-positive myofibroblasts (8, 9), produce increased amounts of collagen, and, through their contractile activities, distort the pa-renchymal lung architecture (9, 10). Furthermore, in contrast to normal resolution of the repair process, in which fibroblasts and myofibroblasts are eliminated by apoptosis (11), in situ studies with fibrotic lung tissues from IPF patients and bleomycin-induced pulmonary fibrosis in mice have shown that fibroblasts and myofibroblasts are resistant to apoptosis and accumulate in the lung parenchyma (12–14). Remarkably, little is known about the physiologic …