Abstract
Fibroblasts perform critical functions during the normal host response to tissue injury, but the inappropriate accumulation and persistent activation of these cells results in the development of tissue fibrosis. The mechanisms accounting for the aberrant accumulation of fibroblasts during fibrotic repair are poorly understood, although evidence supports a role for fibroblast resistance to apoptosis as a contributing factor. We have shown that TGF-β1 and endothelin-1 (ET-1), soluble mediators implicated in fibrogenesis, promote fibroblast resistance to apoptosis. Moreover, we recently found that ET-1 induced apoptosis resistance in normal lung fibroblasts through the upregulation of survivin, a member of the Inhibitor of Apoptosis (IAP) protein family. In the current study, we sought to determine the role of survivin in the apoptosis resistance of primary fibroblasts isolated from the lungs of patients with Idiopathic Pulmonary Fibrosis (IPF), a fibrotic lung disease of unclear etiology for which there is no definitive therapy. First, we examined survivin expression in lung tissue from patients with IPF and found that there is robust expression in the fibroblasts residing within fibroblastic foci (the "active" lesions in IPF which correlate with mortality). Next, we show that survivin expression is increased in fibroblasts isolated from IPF lung tissue compared to cells from normal lung tissue. Consistent with a role in fibrogenesis, we demonstrate that TGF-β1 increases survivin expression in normal lung fibroblasts. Finally, we show that inhibition of survivin enhances susceptibility of a subset of IPF fibroblasts to apoptosis. Collectively, these findings suggest that increased survivin expression represents one mechanism contributing an apoptosis-resistant phenotype in IPF fibroblasts.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by the progressive development of scar tissue which can lead to respiratory failure and death
We examined the role of survivin in the regulation of IPF lung fibroblast apoptosis
We show that survivin expression is increased in the mesenchymal cells within the fibroblastic foci of IPF lungs, supporting a role for this Inhibitor of Apoptosis (IAP) in the apoptosis-resistant phenotype of these cells
Summary
Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by the progressive development of scar tissue which can lead to respiratory failure and death. The incidence of IPF is increasing and, with an average survival of 2 - 3 years following the diagnosis, the overall prognosis is poor [1,2,3]. Despite the generally poor prognosis, a well-recognized clinical feature of IPF is the markedly heterogeneous clinical course, with some patients maintaining stable lung function for years while others experience a rapid deterioration culminating in respiratory failure and death within months of the diagnosis [5]. Alveolar scarring in IPF is hypothesized to result from dysfunctional wound repair which is characterized by the accumulation of mesenchymal cells (including fibroblasts and their differentiated phenotype, myofibroblasts) within pathologic lesions called fibroblastic foci [7,8]. During normal reparative responses following injury, mesenchymal cells perform critical functions which provide healing wounds with tensile strength and facilitate the homeostatic restoration of epithelial integrity, including the synthesis, secretion, organization and con-
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