title: Use of consomic rats for genomic insights into ventilator-associated lung injury.
abstract: Increasing evidence supports the contribution of genetic influences on susceptibility/severity in acute lung injury (ALI), a devastating syndrome requiring mechanical ventilation with subsequent risk for ventilator-associated lung injury (VALI). To identify VALI candidate genes, we determined that Brown Norway (BN) and Dahl salt-sensitive (SS) rat strains were differentially sensitive to VALI (tidal volume of 20 ml/kg, 85 breaths/min, 2 h) defined by bronchoalveolar lavage (BAL) protein and leukocytes. We next exploited differential sensitivities and phenotyped both the VALI-sensitive BN and the VALI-resistant SS rat strains by expression profiling coupled to a bioinformatic-intense candidate gene approach (Significance Analysis of Microarrays, i.e., SAM). We identified 106 differentially expressed VALI genes representing gene ontologies such as "transcription" and "chemotaxis/cell motility." We mapped the chromosomal location of the differentially expressed probe sets and selected consomic SS rats with single BN introgressions of chromosomes 2, 13, and 16 (based on the highest density of probe sets) while also choosing chromosome 20 (low probe sets density). VALI exposure of consomic rats with introgressions of BN chromosomes 13 and 16 resulted in significant increases in both BAL cells and protein (compared to parental SS strain), whereas introgression of BN chromosome 2 displayed a large increase only in BAL protein. Introgression of BN chromosome 20 had a minimal effect. These results suggest that genes residing on BN chromosomes 2, 13, and 16 confer increased sensitivity to high tidal volume ventilation. We speculate that the consomic-microarray-SAM approach is a time- and resource-efficient tool for the genetic dissection of complex diseases including VALI.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Nonas
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Liliana Moreno
authors.initials: LM
authors.lastname: Vinasco
authors.forename: Shwu Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.forename: Lee
authors.initials: L
authors.lastname: Sam
authors.forename: Shui Q
authors.initials: SQ
authors.lastname: Ye
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Joe
authors.initials: J
authors.lastname: Barnard
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Grigoryev
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D019295:Computational Biology; D004195:Disease Models, Animal; D023281:Genomics / Q000379:methods*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D013045:Species Specificity