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23 IDENTIFICATION OF ORGAN-SHARED AND STRAIN-INDEPENDENT CANDIDATE GENES DURING COMBINED VENTILATOR-ASSOCIATED LUNG AND KIDNEY INJURY.
  1. D. N. Grigoryev1,
  2. S. Sammani2,
  3. S.-F. Ma2,
  4. S. Q. Ye2,
  5. K. C. Barnes1,
  6. H. Rabb1,
  7. J. G.N. Garcia2
  1. 1Johns Hopkins University, Baltimore, MD;
  2. 2The University of Chicago, Chicago, IL

Abstract

Combined ventilator-induced lung injury (VILI) and acute renal failure (ARF) have 80% mortality in the ICU. We hypothesized that analysis of global genetic changes in lung and kidney tissues during developing of ALI will identify similar genomic responses to injury that could underlie injurious effects in both organs. We performed gene expression profiling of lung and kidney tissues in three different mouse strains in a model of VILI, speculating that key transcriptional changes would be tissue and strain independent. Three inbred mouse strains C57BL/6J (B), C3H/HeJ (H), and DBA/2J (D) were selected and young 4-week-old mice were mechanically ventilated (Vt = 17 mL/kg, 110 breaths/min) for 2 hours (n = 6-8) and compared to spontaneous ventilated (n = 6) mice. Analysis of bronchoalveolar lavage proteins demonstrated a significant (p < .05) increase in B, H, and D strains by 133 ± 47SE μg/mL, 125 ± 28SE μg/mL, and 108 ± 53SE μg/mL, respectively, with no significant differences between groups at this age. Gene expression profiles of VILI-affected lung and kidney tissues were generated using MG-U74A (12,488 genes) GeneChips (n = 12) and simultaneously analyzed using GC-Robust Multichip Average and Significance Analysis of Microarrays softwares. Genes with the lowest false discovery rate (q = 0.092%) and ± 50% fold change (FC) were considered affected by VILI in both tissues. Gene Ontology (GO) analysis of identified genes was conducted by GenMAPP and MAPPFinder tools and biological processes with z score > 1.96 were considered significantly affected by VILI. This cross-tissue and cross-strain analysis identified 58 genes that behaved similarly in lung and kidney tissues during VILI. Gene ontology analysis of these genes revealed significant up-regulation of genes involved in response to stress (z = 2.51), including Mig-6 (5.97FCLung (L), 3.02FCKidney (K)) and Gadd-45{g (3.68FCL, 6.06FCK); and transcription activity (z = 4.04), including Ceb/pd} (3.97FCL, 3.74FCK) and Ceb/pb (2.87FCL, 4.58FCK). These data demonstrate that VILI activates specific transcription factors and stress responsive genes in both lung and kidney in all tested strains. Detailed studies of these pathways can reveal organ-shared VILI targets for the development of new therapeutic strategies for this devastating disorder.

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