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Acute lung injury can result from distinct insults, such as sepsis, ischemia-reperfusion, and ventilator-induced lung injury. Physiologic and morphologic manifestations of disparate forms of injury are often indistinguishable. We sought to demonstrate that acute lung injury resulting from distinct insults may lead to different gene expression profiles.Microarray analysis was used to examine early molecular events in lungs from three rat models of acute lung injury: lipopolysaccharide, hemorrhage shock/resuscitation, and high-volume ventilation.University laboratory.Male Sprague-Dawley rats (body weight, 300-350 g).Rats were subjected to hemorrhagic shock or lipopolysaccharide followed by resuscitation or were subjected to sham operation. First hit was followed by ventilation with either low (6 mL/kg) or high (12 mL/kg) tidal volume for 4 hrs.Physiologic and morphologic variables were assessed. Total RNA was hybridized to Affymetrix chips. Bioconductor was used to identify significantly altered genes. Functional enrichment predictions were performed in Gene Ontology Tree Machine. Confirmation studies included real-time polymerase chain reaction, Western blots, and immunohistochemistry. Physiologic and morphologic variables were noncontributory in determining the cause of acute lung injury. In contrast, molecular analysis revealed unique gene expression patterns that characterized exposure to lipopolysaccharide and high-volume ventilation. We used hypergeometric probability to demonstrate that specific functional enrichment groups were regulated by biochemical vs. biophysical factors. Genes stimulated by lipopolysaccharide were involved in metabolism, defense response, immune cell proliferation, differentiation and migration, and cell death. In contrast, high-volume ventilation led to the regulation of genes involved primarily in organogenesis, morphogenesis, cell cycle, proliferation, and differentiation.These results demonstrate the application of functional genomics to the molecular "fingerprinting" of acute lung injury and the potential for decoupling biophysical from biochemical injury.