Genetic susceptibility to irritant-induced  acute lung injury in mice

Wesselkamper, Scott C.; Prows, Daniel R.; Biswas, Pratim; Willeke, Klaus; Bingham, Eula; Leikauf, George D.

doi:10.1152/ajplung.2000.279.3.l575

Cited by 60 publications

(48 citation statements)

References 46 publications

(44 reference statements)

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“…Ozone, one of the most potent oxidants known (13), quickly produces a pulmonary response in inbred mice that resembles the exudative phase of ARDS; at doses greater than or equal to 4 ppm, ozone causes death within 2 days (14). In contrast to the rapid time course of ozone, nickel (15) and hyperoxia (16,17) can induce ALI mortality within 3 to 4 days in sensitive strains, but resistant strains of mice can survive as long as 10 to 12 days. Importantly, at a time just before their respective mean survival times (MSTs), certain pathologies of ozone-, nickel-, and hyperoxiainduced ALIs are similar in various inbred mouse strains (18,19), suggesting a possible overlap in the injury response to the different oxidants.…”

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Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Prows

Hafertepen²,

Winterberg³

et al. 2008

Am J Respir Cell Mol Biol

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Acute lung injury (ALI) is a devastating condition resulting from diverse causes. Genetic studies of human populations indicate that ALI is a complex disease with substantial phenotypic variance, incomplete penetrance, and gene-environment interactions. To identify genes controlling ALI mortality, we previously investigated mean survival time (MST) differences between sensitive A/J (A) and resistant C57BL/6J (B) mice in ozone using quantitative trait locus (QTL) analysis. MST was significantly linked to QTLs (Aliq1-3) on chromosomes 11, 13, and 17, respectively. Additional QTL analyses of separate and combined backcross and F 2 populations supported linkage to Aliq1 and Aliq2, and established significance for previously suggestive QTLs on chromosomes 7 and 12 (named Aliq5 and Aliq6, respectively). Decreased MSTs of corresponding chromosome substitution strains (CSSs) verified the contribution of most QTL-containing chromosomes to ALI survival. Multilocus models demonstrated that three QTLs could explain the MST difference between progenitor strains, agreeing with calculated estimates for number of genes involved. Based on results of QTL genotype analysis, a double CSS (B.A-6,11) was generated that contained Aliq1 and Aliq4 chromosomes. Surprisingly, MST and pulmonary edema after exposure of B.A-6,11 mice were comparable to B mice, revealing an unpredicted loss of sensitivity compared with separate CSSs. Reciprocal congenic lines for Aliq1 captured the corresponding phenotype in both background strains and further refined the QTL interval. Together, these findings support most of the previously identified QTLs linked to ALI survival and established lines of mice to further resolve Aliq1.Keywords: acute respiratory distress syndrome; chromosome substitution strain; congenic; mean survival; pulmonary edema Acute lung injury (ALI), resulting from both pulmonary and extrapulmonary insults (1-3), is a common outcome of diverse injuries. Although painstaking clinical research has investigated an ever-increasing number of viable candidate genes as potential therapeutic targets, little headway has been made to impact the survival rates of patients with ALI or acute respiratory distress syndrome (ARDS), the most severe manifestation of the disease (4-6). A recent report estimated an annual U.S. mortality rate of 74,500/year and 59,000/year for ALI and ARDS, respectively (6).To complement recent studies of ALI/ARDS candidate genes in human populations (7-12), we initiated studies in inbred mice aimed at identifying the genetic factors controlling ALI. Because our long-term goal is to improve mortality rates, survival time from oxidant-induced ALI has been a common theme used as the quantitative trait (phenotype). Ozone, one of the most potent oxidants known (13), quickly produces a pulmonary response in inbred mice that resembles the exudative phase of ARDS; at doses greater than or equal to 4 ppm, ozone causes death within 2 days (14). In contrast to the rapid time course of ozone, nickel (15) and hyperoxia (16, 17) can i...

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confidence: 99%

Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Prows

Hafertepen²,

Winterberg³

et al. 2008

Am J Respir Cell Mol Biol

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“…What underlies the now recognized healthcare disparity observed in ALI and sepsis outcomes in AfricanAmericans? Although the answers to these queries are incomplete, recent genetic associations strongly suggest that genetic variations, or gene polymorphisms, contribute to ALI susceptibility and severity in a racial-and ethnic-specific manner (20,25,28).Search for susceptibility genes in ALI Ventilation-associated lung injury. There have been many challenges in the search for susceptibility genes on ALI and ventilation-associated lung injury (VALI), such as the heterogeneity in the phenotype (susceptibility and outcome), complex gene-environment interactions, possible incomplete penetrance, and locus heterogeneity.…”

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Genomic insights into acute inflammatory lung injury

Garcia

Vinasco

2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute lung injury (ALI) is a devastating syndrome (usually associated with sepsis) that represents a major healthcare burden in the United States. We have focused our studies on unraveling the genetic underpinnings of this syndrome utilizing a candidate gene approach to identify novel genes for ALI susceptibility. Two novel genes identified by this approach include pre-B cell colony-enhancing factor (PBEF) and the gene for myosin light chain kinase (MLCK). PBEF protein levels were elevated in human bronchoalveolar lavage and serum samples from patients with ALI, and DNA sequencing identified two single nucleotide polymorphisms in the PBEF promoter (T-1001G, C-1543T) that were overrepresented in patients with sepsis-induced ALI. More recently, we found MLCK single polymorphisms and haplotypes to be associated with human ALI with unique variants observed in African-Americans with ALI. Thus genomic and genetic approaches represent powerful strategies in the identification of novel candidate genes and potential targets for ALI therapies. acute respiratory distress syndrome; mechanical ventilation; single nucleotide polymorphisms; haplotype ACUTE LUNG INJURY (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory lung syndromes characterized by diffuse alveolar infiltration, hypoxemia, respiratory failure, and deaths due to multiorgan failure. Mortality rates in ARDS, the most severe ALI clinical scenario, range from 34 to 58% (13) with ϳ150,000 -200,000 ALI cases per year in the United States (27) and an incidence of 17-34 cases/100,000 people per year in Europe, Australia, and other developed countries. Thus ALI and ARDS constitute a major healthcare burden due to the intensive and often prolonged intensive care unit (ICU) hospitalizations. In addition to these epidemiologic studies, race and gender differences in ARDS deaths in the United States over the past several decades have clearly demonstrated an increase in incidence and mortality due to sepsis and ALI in African-Americans when compared with Caucasians (16).ALI is usually caused by sepsis, acid inhalation, or trauma with mechanical ventilation, an intervention strategy commonly used in the ICU to treat ALI, potentially exacerbating ALI pathophysiology and reducing survival if excessive (22,24,10). The hallmarks for ALI, i.e., cellular and spatial heterogeneity, profound high permeability, leukocyte influx, and lung edema, are often augmented by mechanical ventilation in animal models of ALI (30) and are contributing factors for death due to multiorgan failure (23).Genetics/genomics. Over the past several decades, a lingering issue of concern for critical care physicians has been the enormous heterogeneity in the outcomes observed in the care of the ALI/ARDS patient. Why do some conventionally ventilated ARDS patients recover quickly with rapid extubation, whereas other ARDS patients progress to multiorgan failure and death? What underlies the now recognized healthcare disparity observed in ALI and sepsis outcomes in AfricanAmericans? Although...

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“…Haplotype mapping, using a large, genetically diverse panel of inbred murine strains (50)(51)(52), has emerged as a valuable tool to identify the genes responsible for complex traits (53)(54)(55)(56)(57)(58)(59). Recently, we used this method to identify the genetic determinants of acrolein-induced lung injury (59).…”

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confidence: 99%

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

Leikauf

Pope-Varsalona

Concel

et al. 2012

Am J Respir Cell Mol Biol

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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.

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Genetic susceptibility to irritant-induced acute lung injury in mice

Cited by 60 publications

References 46 publications

Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Genomic insights into acute inflammatory lung injury

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

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