Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal disease and characterized by increased deposition of extracellular matrix proteins and scar formation in the lung, resulting from alveolar epithelial damage and accumulation of inflammatory cells. Evidence suggests that Caveolin-1 (Cav-1), a major component of caveolae which regulates cell signaling and endocytosis, is a potential target to treat fibrotic diseases, although the mechanisms and responsible cell types are unclear. We show that Cav-1 expression was downregulated both in alveolar epithelial type I cells in bleomycin-injured mouse lungs and in lung sections from IPF patients. Increased expression of IL-1β and caspase-1 has been observed in IPF patients, indicating inflammasome activation associated with IPF. Gene transfer of a plasmid expressing Cav-1 using transthoracic electroporation reduced infiltration of neutrophils and monocytes/macrophages and protected from subsequent bleomycin-induced pulmonary fibrosis. Overexpression of Cav-1 suppressed bleomycin- or silica-induced activation of caspase-1 and maturation of pro-IL-1β to secrete cleaved IL-1β both in mouse lungs and in primary type I cells. These results demonstrate that gene transfer of Cav-1 downregulates inflammasome activity and protects from subsequent bleomycin-mediated pulmonary fibrosis. This indicates a pivotal regulation of Cav-1 in inflammasome activity and suggests a novel therapeutic strategy for patients with IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal disease and characterized by increased deposition of extracellular matrix proteins and scar formation in the lung, resulting from alveolar epithelial damage and accumulation of inflammatory cells
Cav-1 is downregulated in alveolar epithelial type I cells in a bleomycin-induced pulmonary fibrosis mouse model
Others have reported that Cav-1 expression is reduced in samples of both experimental animal models of pulmonary fibrosis and patients with IPF26,28,33, we determined in which cell type Cav-1 was altered in our bleomycin-mediated pulmonary fibrosis mouse model (Fig. 1)
Summary
Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal disease and characterized by increased deposition of extracellular matrix proteins and scar formation in the lung, resulting from alveolar epithelial damage and accumulation of inflammatory cells. Overexpression of Cav-1 suppressed bleomycin- or silica-induced activation of caspase-1 and maturation of pro-IL-1β to secrete cleaved IL-1β both in mouse lungs and in primary type I cells These results demonstrate that gene transfer of Cav-1 downregulates inflammasome activity and protects from subsequent bleomycin-mediated pulmonary fibrosis. Caveolin-1 (Cav-1) is a major protein component of caveolae and is highly expressed in a variety of cell types in the lung, including alveolar epithelial type I cells, endothelial cells, fibroblasts, and leukocytes[16] It is associated with the regulation of numerous signaling pathways, including mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, resulting in cell growth suppression and induction of apoptosis. The exact nature and mechanism of Cav-1’s role in pulmonary fibrosis remain open
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