Acute kidney injury (AKI) is associated with significant mortality, which increases further when combined with acute lung injury. Experiments in rodents have shown that kidney ischemia-reperfusion injury (IRI) facilitates lung injury and inflammation. To identify potential ischemia-specific lung molecular pathways involved, we conducted global gene expression profiling of lung 6 or 36 h following 1) bilateral kidney IRI, 2) bilateral nephrectomy (BNx), and 3) sham laparotomy in C57BL/6J mice. Bronchoalveolar lavage fluid analysis revealed increased total protein, and lung histology revealed increased cellular inflammation following IRI, but not BNx, compared with sham controls. Total RNA from whole lung was isolated and hybridized to 430MOEA (22,626 genes) GeneChips (n = 3/group), which were analyzed by robust multichip average and significance analysis of microarrays and linked to gene ontology (GO) terms using MAPPFinder. The microarray power analysis predicted that the false discovery rate (q < 1%) and > or =50%-fold change compared with sham would represent significant changes in gene expression. Analysis identified 266 and 455 ischemia-specific, AKI-associated lung genes with increased expression and 615 and 204 with decreased expression at 6 and 36 h, respectively, compared with sham controls. Real-time PCR analysis validated select array changes in lung serum amyloid A3 and endothelin-1. GO analysis revealed significant activation (Z > 1.95) of several proinflammatory and proapoptotic biological processes. Ischemic AKI induces functional and transcriptional changes in the lung distinct from those induced by uremia alone. Further investigation using this lung molecular signature induced by kidney IRI will provide mechanistic insights and new therapies for critically ill patients with AKI.