Integrative assessment of chlorine-induced acute lung injury in mice

George D. Leikauf, Hannah Pope-Varsalona, Vincent J. Concel, Pengyuan Liu, Kiflai Bein, Annerose Berndt, Timothy M. Martin, Koustav Ganguly, An Soo Jang, Kelly A. Brant, Richard A. Dopico, Swapna Upadhyay, Y. P.Peter Di, Qian Li, Zhen Hu, Louis J. Vuga, Mario Medvedovic, Naftali Kaminski, Ming You, Danny C. AlexanderJonathan E. McDunn, Daniel R. Prows, Daren L. Knoell, James P. Fabisiak

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using ≥ 10% allelic frequency and ≥ 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4.

Original languageEnglish (US)
Pages (from-to)234-244
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number2
DOIs
StatePublished - Aug 1 2012

Keywords

  • ARDS
  • Countermeasures
  • Genetics
  • Glutamine
  • Metabolomics

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Leikauf, G. D., Pope-Varsalona, H., Concel, V. J., Liu, P., Bein, K., Berndt, A., Martin, T. M., Ganguly, K., Jang, A. S., Brant, K. A., Dopico, R. A., Upadhyay, S., Di, Y. P. P., Li, Q., Hu, Z., Vuga, L. J., Medvedovic, M., Kaminski, N., You, M., ... Fabisiak, J. P. (2012). Integrative assessment of chlorine-induced acute lung injury in mice. American journal of respiratory cell and molecular biology, 47(2), 234-244. https://doi.org/10.1165/rcmb.2012-0026OC