title: Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis.
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.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago 60612, USA.
authors.forename: Ni
authors.initials: N
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Gufang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago 60612, USA.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Liang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Heaven, CT 06510, USA.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.|Institute of Chinese Medical Sciences and the State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001761:Bleomycin; D018925:Chemokines / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D011014:Pneumonia / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; C511197:PREX1 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein