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ER Stress‐BiP Axis Regulates Endothelial Barrier Dysfunction and Inflammation in Acute Lung Injury
Author(s) -
Leonard Antony,
Rahman Arshad,
Grose Valerie,
Slavin Spencer,
Fazal Fabeha
Publication year - 2016
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.30.1_supplement.980.13
Subject(s) - unfolded protein response , inflammation , proinflammatory cytokine , lipopolysaccharide , medicine , endoplasmic reticulum , immunology , pharmacology , cancer research , chemistry , biochemistry
Recent Studies have provided evidence of associations between endoplasmic reticulum (ER) stress and human diseases. Aberrant regulation of ER stress is associated with many chronic inflammatory diseases including type 2 diabetes, inflammatory bowel disease (IBD), cancer, rheumatoid arthritis, atherosclerosis, and chronic obstructive pulmonary disease (COPD). However, the role of ER stress and ER chaperone BiP/GRP78 in acute inflammatory injury, particularly in the context of lung endothelium, is poorly defined. We provide novel evidence that implicates ER stress‐BiP axis as a critical determinant of EC barrier disruption and inflammation associated with acute lung injury (ALI). Our data show that stimulation of endothelial cells (EC) with thrombin caused an increase in BiP levels and pretreatment of cells with ER stress inhibitor 4‐phenylbutyric acid (4‐PBA) prevented this response. Inhibition of ER stress by this approach also decreased thrombin‐induced levels of proinflammtory mediators ICAM‐1, IL‐6, and IL‐8. Consistent with this, pretreatment of EC with AB5 cytotoxin family member subtilase (SubAB), which selectively cleaves and inactivates BiP inhibited thrombin‐induced elevation of intracellular Ca 2+ , a critical requirement in the mechanism of EC permeability and inflammation. Importantly, BiP inactivation also protected against thrombin‐induced VE‐cadherin disassembly and EC permeability. We determined the in vivo relevance of BiP in ALI by monitoring the effect of SubAB on lung inflammation and injury in an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI. We found a marked decrease in LPS‐induced lung PMN sequestration and microvascular leakage in mice treated with SubAB. Together these data identify ER‐BiP axis as a novel regulator of EC dysfunction in ALI. Support or Funding Information (Supported by: NIH (HL096907 and HL116632)