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Role of endoplasmic reticulum chaperone protein BiP in endotoxin‐induced acute lung injury (669.10)
Author(s) -
Fazal Fabeha,
Schwarzenbart Amanda,
Leonard Antony
Publication year - 2014
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.28.1_supplement.669.10
Subject(s) - endoplasmic reticulum , unfolded protein response , bronchoalveolar lavage , inflammation , chemical chaperone , chemistry , pathogenesis , microbiology and biotechnology , secretion , immunology , medicine , lung , biology , biochemistry
Endoplasmic reticulum (ER) makes up approximately 10% of the cell volume and plays an important role in multiple cellular processes such as calcium homeostasis, protein synthesis, folding and secretion, and lipid biosynthesis. Disturbances in ER homeostasis result in ER stress, which is implicated in a wide range of pathological conditions such as ischemic injury, neurodegenerative disorders, metabolic diseases and more recently in inflammatory conditions. A key step in the pathogenesis of acute lung injury (ALI), an inflammatory disease, involves alveolarcapillary membrane injury. This leads to infiltration of inflammatory cells into the alveolar airspaces and increased permeability, resulting in pulmonary edema. In this study, we report a critical role for ER chaperone and signaling regulator BiP in LPS‐induced ALI. Our data shows that AB5 cytotoxin family member subtilase cytotoxin (SubAB), which selectively cleaves and inactivates BiP, triggers ER stress and protects mice from endotoxin‐induced lung injury. In WT mice, LPS inhalation induced significant polymorphonuclear leukocyte (PMN) recruitment into bronchoalveolar lavage (BAL); however, mice pretreated to intraperitoneal injection of SubAB were protected from PMN influx into the alveolar airspaces. Consistently, LPS‐induced level of adhesion protein ICAM‐1, which plays a critical role in PMN adhesion and endothelial transmigration, was also reduced in SubAB treated mice. In addition, LPS‐induced microvascular permeability was restored upon SubAB pretreatment, as evidenced by a marked decrease in the level of albumin in the BAL. In contrast, SubAA272B, a SubAB active site mutant that cannot induce ER stress, failed to show the protective effect. These findings suggest that preconditioning the mice with ER stress ameliorates ALI caused by LPS. Grant Funding Source : NIH