Clara cell secretory protein and phospholipase A2activity modulate acute ventilator-induced lung injury in mice

Abstract

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA2(cPLA2) and Clara cell secretory protein (CCSP), a modulator of cPLA2activity, we compared lung injury with and without a PLA2inhibitor in wild-type mice and CCSP-null mice (CCSP−/−) ventilated with high and low peak inflation pressures (PIP) for 2- or 4-h periods. After ventilation with high PIP, we observed significant increases in the bronchoalveolar lavage albumin concentrations, lung wet-to-dry weight ratios, and lung myeloperoxidase in both genotypes compared with unventilated controls and low-PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP−/−mice relative to wild-type mice. Inhibition of cPLA2in wild-type and CCSP−/−mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype. Membrane phospho-cPLA2and cPLA2activities were significantly elevated in lung homogenates of high-PIP ventilated mice of both genotypes but were significantly higher in the CCSP−/−mice relative to the wild-type mice. Inhibition of cPLA2significantly attenuated both the phospho-cPLA2increase and increased cPLA2activity due to high-PIP ventilation. We propose that mechanical activation of the cPLA2pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2pathway and reduction of proinflammatory products produced by this pathway.