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1 Surgery, Johns Hopkins, Baltimore, Maryland, United States
2 Clinical Immunology, Johns Hopkins, Baltimore, Maryland, United States
3 Medicine-renal, Johns Hopkins University, Baltimore, Maryland, United States
4 Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
5 Medicine/Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: hhassou1{at}jhmi.edu.
Acute kidney injury (AKI) is associated with significant mortality, which increases further when combined with acute lung injury (ALI). 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 hours following 1) bilateral kidney IRI, 2) bilateral nephrectomy (BNx), and 3) sham laparotomy in C57BL/6J mice. Bronchoalveolar lavage fluid analysis revealed increased protein, and lung histology revealed increased inflammation following IRI, but not BNx, when compared to sham. RNA from whole lung was isolated and hybridized to 430MOEA (22,626 genes) GeneChips (n=3/group) which were analyzed by Robust Multichip Average (RMA) and Significance Analysis of Microarrays (SAM), and linked to gene ontology (GO) terms using MAPPFinder. The microarray power analysis predicted that false discovery rate (q<1%) and 
50% fold change compared to 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 hours, respectively, when compared to sham. 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 pro-inflammatory and pro-apoptotic biological processes. Ischemic AKI induces functional and transcriptional changes in the lung distinct from those induced by uremia alone. Further investigation using this kidney IRI-induced lung molecular signature may provide mechanistic insights and new therapies for critically ill patients with AKI.
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