title: Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury.
abstract: Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, 60612, USA.
authors.forename: Dejie
authors.initials: D
authors.lastname: Liu
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.forename: David E
authors.initials: DE
authors.lastname: Schwartz
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Chen
authors.forename: Guochang
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000201:enzymology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D012122:Ventilators, Mechanical / Q000009:adverse effects
chemical_list: D006023:Glycoproteins; C039304:calpain inhibitors; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D002154:Calpain; C112682:Capn1 protein, mouse; C570925:Capn2 protein, mouse