Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA(2) (cPLA(2)) and Clara cell secretory protein (CCSP), a modulator of cPLA(2) activity, we compared lung injury with and without a PLA(2) inhibitor 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 cPLA(2) in 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-cPLA(2) and cPLA(2) activities 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 cPLA(2) significantly attenuated both the phospho-cPLA(2) increase and increased cPLA(2) activity due to high-PIP ventilation. We propose that mechanical activation of the cPLA(2) pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA(2) pathway and reduction of proinflammatory products produced by this pathway.