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ADAM15 cytoplasmic domain‐mediated Src signaling in lung endothelial barrier dysfunction during septic injury
Author(s) -
Sun Chongxiu,
Rigor Robert,
Guo Mingzhang,
Lee Eugene,
Wu Mack,
Yuan Sarah
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1101.8
Subject(s) - proto oncogene tyrosine protein kinase src , lung , microbiology and biotechnology , medicine , cancer research , signal transduction , biology
ADAM15 is a disintegrin and metalloprotease implicated in inflammation. This study was to evaluate its role in mediating endothelial barrier dysfunction during septic injury. Histopathology and immunoblotting demonstrated increased ADAM15 expression in the lungs of pneumonia patients. In a mouse model of LPS –induced endotoxicosis, upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration, which was attenuated in adam15−/− mice. Molecular assays employing siRNA knockdown confirmed the causal effect of ADAM15 on albumin permeability and neutrophil transmigration across endothelial barriers. To examine domain‐related functions, several ADAM15 mutants were constructed. Overexpression of proteolytically dead metalloproteinase, or RGD mutation in the disintegrin domain produced hyperpermeability to the same extent as wild type; however, truncation of the C‐terminus failed to induce barrier dysfunction. Further imaging and molecular analyses revealed that the ADAM15‐induced barrier dysfunction was mediated by Src‐dependent junction protein tyrosine phosphorylation and g‐catenin dissociation from VE‐cadherin. We suggest that ADAM15 upregulation contributes to acute lung injury by causing endothelia hyperpermeability through its cytoplasmic domain potentially invovlving Src‐signaling. Supported by NIH HL61507, HL84542, and HL96640.