title: Functional genomics of oxidant-induced lung injury.
abstract: In summary, acute lung injury is a severe (>40% mortality) respiratory disease associated with numerous precipitating factors. Despite extensive research since its initial description over 30 years ago, questions remain about the basic pathophysiological mechanisms and their relationship to therapeutic strategies. Histopathology reveals surfactant disruption, epithelial perturbation and sepsis, either as initiating factors or as secondary complications, which in turn increase the expression of cytokines that sequester and activate inflammatory cells, most notably, neutrophils. Concomitant release of reactive oxygen and nitrogen species subsequently modulates endothelial function. Together these events orchestrate the principal clinical manifestations of the syndrome, pulmonary edema and atelectasis. To better understand the gene-environmental interactions controlling this complex process, we examined the relative sensitivity of inbred mouse strains to acute lung injury induced by ozone, ultrafine PTFE, or fine particulate NiSO4 (0.2 microm MMAD, 15-150 microg/m3). Measuring survival time, protein and neutrophils in bronchoalveolar lavage, lung wet: dry weight, and histology, we found that these responses varied between inbred mouse strains, and susceptibility is heritable. To assess the molecular progression of NiSO4-induced acute lung injury, temporal relationships of 8734 genes and expressed sequence tags were assessed by cDNA microarray analysis. Clustering of co-regulated genes (displaying similar temporal expression patterns) revealed the altered expression of relatively few genes. Enhanced expression occurred mainly in genes associated with oxidative stress, anti-proteolytic function, and repair of the extracellular matrix. Concomitantly, surfactant proteins and Clara cell secretory protein mRNA expression decreased. Genome wide analysis of 307 mice generated from the backcross of resistant B6xA F1 with susceptible A strain identified significant linkage to a region on chromosome 6 (proposed as Aliq4) and suggestive linkages on chromosomes 1, 8, and 12. Combining of these QTLs with two additional possible modifying loci (chromosome 9 and 16) accounted for the difference in survival time noted in the A and B6 parental strains. Combining these findings with those of the microarray analysis has enabled prioritization of candidate genes. These candidates, in turn, can be directed to the lung epithelium in transgenic mice or abated in inducible and constitutive gene-targeted mice. Initial results are encouraging and suggest that several of these mice vary in their susceptibility to oxidant-induced lung injury. Thus, these combined approaches have led to new insights into functional genomics of lung injury and diseases.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Ohio, USA. leikaugd@uc.edu
authors.forename: G D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: S A
authors.initials: SA
authors.lastname: McDowell
authors.forename: C J
authors.initials: CJ
authors.lastname: Bachurski
authors.forename: B J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: K
authors.initials: K
authors.lastname: Gammon
authors.forename: S C
authors.initials: SC
authors.lastname: Wesselkamper
authors.forename: W
authors.initials: W
authors.lastname: Hardie
authors.forename: J S
authors.initials: JS
authors.lastname: Wiest
authors.forename: J E
authors.initials: JE
authors.lastname: Leikauf
authors.forename: T R
authors.initials: TR
authors.lastname: Korfhagen
authors.forename: D R
authors.initials: DR
authors.lastname: Prows
mesh_terms: D000818:Animals; D004781:Environmental Exposure / Q000009:adverse effects*; D004815:Epidermal Growth Factor / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006801:Humans; D055370:Lung Injury; D009532:Nickel / Q000009:adverse effects; D016877:Oxidants / Q000009:adverse effects*; D010126:Ozone / Q000009:adverse effects; D011138:Polytetrafluoroethylene / Q000009:adverse effects; D019655:Quantitative Trait, Heritable; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D016877:Oxidants; D016211:Transforming Growth Factor alpha; C029938:nickel sulfate; D004815:Epidermal Growth Factor; D010126:Ozone; D009532:Nickel; D011138:Polytetrafluoroethylene