Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced XXXX .

@entity18336 @entity55 @entity19 @entity4 @entity24158 @entity651 @entity281 @entity777 @entity358 @entity842 @entity8024 @entity637 @entity13471
Lung inflammatory responses in the absence of @entity281 are considered to be one of primary mechanisms of ventilator-induced @entity651 . Here, we determined the role of calpain in the pathogenesis of @entity55 attributable to mechanical ventilation. Male C57BL/6J @entity19 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 @entity18336 and @entity24158 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 @entity55 as evidenced by neutrophil recruitment, production of @entity637 and @entity777 , pulmonary vascular hyperpermeability, and lung @entity4 formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by @entity358 . Depletion of @entity18336 or @entity24158 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 @entity842 (NO) synthase ( @entity13471 )-mediated NO production and subsequent @entity8024 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates @entity55 during ventilator-induced @entity651 via @entity13471 /NO-dependent @entity8024 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced @entity651 .
