Abstract
Pulmonary fibrosis (PF) leads to progressive and often irreversible loss of lung functions, posing a health threat with no effective cure. We examined P-Rex1, a PI3K- and G protein βγ-regulated guanine nucleotide exchange factor (GEF) of the Rac small GTPase, for its potential involvement in PF. In a bleomycin-induced PF model, mice deficient in p-rex1 had well-preserved alveolar structure and survived significantly better than their wild type (WT) littermates. The p-rex1−/− mice expressed significantly less proinflammatory cytokines and chemokines and had reduced leukocyte infiltration in the lung tissue than their WT littermates. P-Rex1 was detected in lung fibroblasts of WT mice, and its genetic deletion attenuated TGFβ-1-stimulated lung fibroblast migration, Rac1 activation and p38 MAPK phosphorylation. The p-rex1−/− mice showed significantly reduced pathological changes including the expression of α-smooth muscle actin, fibronectin and TGFβ-1 compared with their WT controls. Expression of a GEF-deficient P-Rex1 mutant effectively blocked Smads-dependent transcriptional activation, suggesting that P-Rex1 is a downstream mediator of TGFβ-1 signaling. These findings identify P-Rex1 as a novel player of PF, suggesting that targeting P-Rex1 may simultaneously block the inflammatory and fibrogenic processes of PF.
Highlights
Pulmonary fibrosis (PF) leads to progressive and often irreversible loss of lung functions, posing a health threat with no effective cure
All forms of PF are characterized by increased synthesis and deposit of extracellular matrix (ECM) proteins including collagen and fibronectin, accompanied by elevated production of transforming growth factor β1 (TGF-β1) and increased proliferation of interstitial fibroblasts[2]
We investigated whether P-Rex[1], a PI3K- and Gβγ-regulated guanine nucleotide exchange factor (GEF) known for its roles in the activation of Rac[7,8], is involved in the development of PF in bleomycin-treated mice
Summary
Pulmonary fibrosis (PF) leads to progressive and often irreversible loss of lung functions, posing a health threat with no effective cure. The fibrogenic response, characterized with fibroblast proliferation and increased production of ECM proteins, begins on day 4 after bleomycin administration and culminates on Day 215 Using this model, several factors that affect the inflammatory and fibrogenic phases of PF have been identified. Mouse survival assay and histological analysis indicate that genetic deletion of p-rex[1] offers protection against bleomycin-induced PF, as evidenced by reduced TGF-β1 production, abrogated fibroblast migration and reduced mortality. These findings offer the possibility of targeting P-Rex[1] for PF therapy based on its dual functions in the inflammatory and fibrogenic processes
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