Use of consomic rats for genomic insights into ventilator-associated lung injury

Stephanie Nonas, Liliana Moreno Vinasco, Shwu Fan Ma, Jeffrey R. Jacobson, Ankit A. Desai, Steven M. Dudek, Carlos Flores, Paul M. Hassoun, Lee Sam, Shui Q. Ye, Jaideep Moitra, Joe Barnard, Dmitry N. Grigoryev, Yves A. Lussier, Joe G N Garcia

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume293
Issue number2
DOIs
StatePublished - Aug 2007
Externally publishedYes

Fingerprint

Lung Injury
Mechanical Ventilators
Norway
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 2
Bronchoalveolar Lavage
Chromosomes, Human, Pair 20
Salts
Tidal Volume
Microarray Analysis
Genes
Inbred Dahl Rats
Gene Ontology
Proteins
Acute Lung Injury
Chemotaxis
Computational Biology
Artificial Respiration
Cell Movement

Keywords

  • Bioinformatics
  • Candidate gene approach
  • Consomics
  • Microarrays
  • Rodent mechanical ventilation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Use of consomic rats for genomic insights into ventilator-associated lung injury. / Nonas, Stephanie; Moreno Vinasco, Liliana; Ma, Shwu Fan; Jacobson, Jeffrey R.; Desai, Ankit A.; Dudek, Steven M.; Flores, Carlos; Hassoun, Paul M.; Sam, Lee; Ye, Shui Q.; Moitra, Jaideep; Barnard, Joe; Grigoryev, Dmitry N.; Lussier, Yves A.; Garcia, Joe G N.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 293, No. 2, 08.2007.

Research output: Contribution to journalArticle

Nonas, S, Moreno Vinasco, L, Ma, SF, Jacobson, JR, Desai, AA, Dudek, SM, Flores, C, Hassoun, PM, Sam, L, Ye, SQ, Moitra, J, Barnard, J, Grigoryev, DN, Lussier, YA & Garcia, JGN 2007, 'Use of consomic rats for genomic insights into ventilator-associated lung injury', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 293, no. 2. https://doi.org/10.1152/ajplung.00481.2006
Nonas, Stephanie ; Moreno Vinasco, Liliana ; Ma, Shwu Fan ; Jacobson, Jeffrey R. ; Desai, Ankit A. ; Dudek, Steven M. ; Flores, Carlos ; Hassoun, Paul M. ; Sam, Lee ; Ye, Shui Q. ; Moitra, Jaideep ; Barnard, Joe ; Grigoryev, Dmitry N. ; Lussier, Yves A. ; Garcia, Joe G N. / Use of consomic rats for genomic insights into ventilator-associated lung injury. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2007 ; Vol. 293, No. 2.
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AB - 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.

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