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1 Department of Physiology, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA
2 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
3 Department of Pediatrics, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA
* To whom correspondence should be addressed. E-mail: jparker{at}usouthal.edu.
Lung vascular permeability is acutely increased by high pressure and volume ventilation. To determine the roles of mechanically activated cytosolic phospholipase A2 (cPLA2) and Clara cell secretory protein (CCSP), a modulator of cPLA2 activity, we compared lung injury with and without a PLA2 inhibitor in wild type mice and CCSP null mice (CCSP(-/-)) ventilated with high and low peak inflation pressures (PIP) for 2 or 4 hour periods. After ventilation with High PIP, we observed significant increases in the bronchoalveolar lavage (BAL) albumin concentrations, lung wet/dry weight ratios, and lung myeloperoxidase in both genotypes compared to unventilated controls and Low PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP(-/-) mice relative to wild type. Inhibition of cPLA2 in wild type and CCSP(-/-) mice ventilated at High PIP for 4 hours significantly reduced BAL albumin and total protein and lung wet/dry weight ratios compared to vehicle treated mice of the same genotype. Membrane phospho-cPLA2 and cPLA2 activities were significantly elevated in lung homogenates of High PIP ventilated mice of both genotypes, but was significantly higher in the CCSP(-/-) mice relative to wild type. Inhibition of cPLA2 significantly attenuated both the phospho-cPLA2 increase and increased cPLA2 activity due to High PIP ventilation. We propose that mechanical activation of the cPLA2 pathway contributes to acute High PIP induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2 pathway and reduction pro-inflammatory products produced by this pathway.
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