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The Genetics of Innate Immunity in the Lung* FREE TO VIEW

Donald N. Cook, PhD; Shuibang Wang, PhD; Gabriel P. Howles, BSc; Marcy Speer, PhD; Gary Churchhill, PhD; John Quackenbush, PhD; David A. Schwartz, MD, MPH, FCCP
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*From the Division of Pulmonary and Critical Care Medicine (Drs. Cook, Speer, and Schwartz, and Mr. Howles), Duke University Medical Center, Durham, NC; The Institute for Genomic Research (Drs. Wang and Quackenbush), Rockville, MD; and Jackson Laboratories (Dr. Churchhill), Bar Harbor, ME.

Correspondence to: Donald N. Cook, PhD, Room 261, MSRB, Box 2629, Duke University Medical Center, Research Dr, Durham, NC 27710; e-mail: cook0054@mc.duke.edu

Chest. 2003;123(3_suppl):369S. doi:10.1378/chest.123.3_suppl.369S
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Lipopolysaccharide elicits a vigorous inflammatory response and has been linked to the progression of asthma and other forms of airway disease. An improved understanding of the innate immune response to lipopolysaccharide should lead to novel therapies to treat these diseases. Towards this end, we challenged 32 recombinant inbred (RI) strains of (C57BL/6J X DBA/2J) [BXD] mice with aerosolized lipopolysaccharide and compared their biological responses by assaying concentrations of tumor necrosis factor-α and polymorphonuclear cells in the lavage fluid. The biological responses of these RI strains ranged from less than the low-responder parental strain C57BL/6J to higher than the high-responder parental strain, DBA/2J. One RI strain was essentially unresponsive to lipopolysaccharide. Phenotypic analysis of F2 offspring from this unresponsive strain suggested these mice have a recessive mutation in a single, unidentified gene.

Spotted complementary DNA microarray analysis was performed on lungs of six selected strains, including the two parental strains and the unresponsive strain. This analysis revealed approximately 50 genes that were consistently induced at least twofold by lipopolysaccharide in the responsive strains. Some, but not all, of these genes have been previously associated with the biological response to lipopolysaccharide. Genes not previously linked to the lipopolysaccharide response might represent novel molecular targets for therapeutic intervention. Most of the genes up-regulated in the responsive strains were unchanged in the unresponsive strain; however, some genes in the latter were also significantly up-regulated, providing clues to the nature of the recessive mutation.

In a parallel study, a quantitative trait locus analysis was performed by relating lipopolysaccharide responses phenotypes of BXD RI mice to their parental strain DNA distribution pattern using the Jackson Laboratories’ Web site (http://www.informatics.jax.org/searches/riset_form.shtml). Quantitative trait locus analyses of each BXD strain revealed suggestive loci that correlate with the biological response to inhaled lipopolysaccharide. Interestingly, some of these loci contain genes identified in the microarray analysis. These genes represent particularly strong candidates for participants in the innate immune response in the lung.

Abbreviation: RI = recombinant inbred

This abstract is funded by National Institutes of Health grants HL66611 and 66604.




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