Aspiration of gastric contents is one of leading causes of the acute respiratory distress syndrome (ARDS). The pathogenesis of acid aspiration-induced acute lung injury is well understood. Less clear is why patients who have suffered acid aspiration are susceptible to ARDS. We studied the effects of acid instillation on the inflammatory response to subsequent lipopolysaccharide (LPS) challenge in rats. Instillation of acid into the right lung worsened the pathology induced by LPS that was administered 24 h after acid instillation. This included worsened oxygenation, increased pulmonary edema, increased production of tumor necrosis factor-alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant, neutrophil accumulation and mobilization to the alveolar spaces, and nitric oxide (NO) production. Of interest, neutrophil mobilization, NO production, and protein permeability were also magnified in the left lung. These effects were attenuated by administration of the protein tyrosine kinase (PTK) inhibitors genistein and tyrphostin AG556. These data suggest that acid instillation primes the rat to enhance the inflammatory response to subsequent endotoxin challenge and that at least part of the augmented inflammatory response depends on PTK.