Adult respiratory distress syndrome (ARDS) is characterized by acute lung injury with a high mortality rate and yet its mechanism is poorly understood. Sepsis syndrome and acid aspiration are the most frequent causes of ARDS, leading to increased lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration and respiratory failure. Using a murine model of acute lung injury induced by septic syndrome or acid aspiration, we investigated the role of cytosolic phospholipase A(2) (cPLA(2)) in ARDS. We found that disruption of the gene encoding cPLA(2) significantly reduced pulmonary edema, PMN sequestration and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration, Acute lung injury induced by acid aspiration was similarly reduced in mice with a disrupted cpla2 gene. Our observations suggest that cPLA(2) is a mediator of acute lung injury induced by sepsis syndrome or acid aspiration,Thus, the inhibition of cPLA(2)-initiated pathways may provide a therapeutic approach to acute lung injury, for which no pharmaceutical agents are currently effective.