Acute Lung Injury: Functional Genomics and Genetic Susceptibility

doi:10.1378/chest.121.3_suppl.70S

Chest

Volume 121, Issue 3, Supplement, March 2002, Pages 70S-75S

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Initiated by numerous factors, acute lung injury is marked by epithelial and endothelial cell perturbation and inflammatory cell influx that leads to surfactant disruption, pulmonary edema, and atelectasis. This syndrome has been associated with a myriad of mediators including cytokines, oxidants, and growth factors. To better understand gene-environmental interactions controlling this complex process, the sensitivity of inbred mouse strains was investigated following acute lung injury that was induced by fine nickel sulfate aerosol. Measuring survival time, protein and neutrophil concentrations in BAL fluid, lung wet-to-dry weight ratio, and histology, we found that these responses varied between inbred mouse strains and that susceptibility is heritable. To assess the progression of acute lung injury, the temporal expression of genes and expressed sequence tags was assessed by complementary DNA microarray analysis. Enhanced expression was noted in genes that were associated with oxidative stress, antiprotease function, and extracellular matrix repair. In contrast, expression levels of surfactant proteins (SPs) and Clara cell secretory protein (ie, transcripts that are constitutively expressed in the lung) decreased markedly. Genome-wide analysis was performed with offspring derived from a sensitive and resistant strain (C57BL/6xA F₁ backcrossed with susceptible A strain). Significant linkage was identified for a locus on chromosome 6 (proposed as Aliq4), a region that we had identified previously following ozone-induced acute lung injury. Two suggestive linkages were identified on chromosomes 1 and 12. Using haplotype analysis to estimate the combined effect of these regions (along with putative modifying loci on chromosomes 9 and 16), we found that five loci interact to account for the differences in survival time of the parental strains. Candidate genes contained in Aliq4 include SP-B, aquaporin 1, and transforming growth factor-α. Thus, the functional genomic approaches of large gene set expression (complementary DNA microarray) and genome-wide analyses continue to provide novel insights into the genetic susceptibility of lung injury.

Section snippets

Results and Discussion

To begin to address the genetic determinants of acute lung injury, we first examined the existing experimental systems in model species. Acute lung injury can be initiated by a diverse array of precipitating factors. Several animal models of acute lung injury have been developed, including induction by lipopolysaccharide, hyperoxia, embolism, and oleic acid.⁸ We have compared the response between inbred mouse strains during continuous exposures to ozone,⁹ ultrafine polytetrafluoroethylene

References (48)

JH Widdicombe et al.
The basic defect in cystic fibrosis
Trends Biochem Sci
(1991)
ES Lander et al.
MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations
Genomics
(1987)
KE Driscoll et al.
Ozone inhalation stimulates expression of the neutrophil chemotactic peptide, MIP-2
Toxicol Appl Pharmacol
(1993)
JM Benson et al.
Particle clearance and histopathology in lungs of F344/N rats and B6C3F1 mice inhaling nickel oxide or nickel sulfate
Fundam Appl Toxicol
(1995)
R Derynck
Transforming growth factor-alpha
Cell
(1988)
A Tarnawski et al.
Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats
Gastroenterology
(1992)
B Egger et al.
Mice lacking transforming growth factor alpha have an increased susceptibility to dextran sulfate-induced colitis
Gastroenterology
(1997)
B Burrows et al.
The time course and prognosis of different forms of chronic airways obstruction in a sample from the general population
N Engl J Med
(1987)
DW Dockery et al.
An association between air pollution and mortality in six U.S. cities
N Engl J Med
(1993)
JM Pilewski et al.
Role of CFTR in airway disease
Physiol Rev
(1999)

ES Lander et al.

Genetic dissection of complex traits

Science

(1994)

JF Lewis et al.

Surfactant and the adult respiratory distress syndrome

Am Rev Respir Dis

(1993)

JF Pittet et al.

Biological markers of acute lung injury: prognostic and pathogenetic significance

Am J Respir Crit Care Med

(1997)

PC Levy et al.

The acute respiratory distress syndrome: current trends in pathogenesis and management

Compr Ther

(1995)

DR Prows et al.

Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice

Nat Genet

(1997)

WD Hardie et al.

Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-α

Am J Physiol Lung Cell Mol Physiol

(1999)

SC Wesselkamper et al.

Genetic susceptibility to irritant-induced acute lung injury in mice

Am J Physiol Lung Cell Mol Physiol

(2000)

DR Prows et al.

Quantitative trait locus analysis of nickel-induced acute lung injury in mice

Am J Respir Cell Mol Biol

(2001)

DR Prows et al.

Ozone-induced acute lung injury: genetic analysis of F₂ mice generated from A/J and C57BL/6J strains

Am J Physiol Lung Cell Mol Physiol

(1999)

SR Kleeberger et al.

Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

Nat Genet

(1997)

E Lander et al.

Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results

Nat Genet

(1995)

JD Marshall et al.

The AXB and BXA set of recombinant inbred mouse strains

Mamm Genome

(1992)

SB Sampson et al.

An edited linkage map for the AXB and BXA recombinant inbred mouse strains

Mamm Genome

(1998)

JL Mu et al.

Strain distribution pattern in AXB and BXA recombinant inbred strains for loci on murine chromosomes 10, 13, 17, and 18

Mamm Genome

(1993)

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: This study was supported by the National Institutes of Health by National Institute of Environmental Health Sciences grants ES06096 and ES10562, and by National Heart, Lung, and Blood Institute grants HL65612 and HL65613. Susan McDowell is a recipient of the Science to Achieve Results Graduate Fellowship and the Ryan Fellowship of the US Environmental Protection Agency, and this work was conducted in partial fulfillment of the requirements for the PhD degree at the University of Cincinnati.

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Chest

Acute Lung Injury: Functional Genomics and Genetic Susceptibility

Section snippets

Results and Discussion

Trends Biochem Sci

Genomics

Toxicol Appl Pharmacol

Fundam Appl Toxicol

Cell

Gastroenterology

Gastroenterology

The time course and prognosis of different forms of chronic airways obstruction in a sample from the general population

N Engl J Med

An association between air pollution and mortality in six U.S. cities

N Engl J Med

Role of CFTR in airway disease

Physiol Rev

Genetic dissection of complex traits

Science

Surfactant and the adult respiratory distress syndrome

Am Rev Respir Dis

Biological markers of acute lung injury: prognostic and pathogenetic significance

Am J Respir Crit Care Med

The acute respiratory distress syndrome: current trends in pathogenesis and management

Compr Ther

Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice

Nat Genet

Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-α

Am J Physiol Lung Cell Mol Physiol

Genetic susceptibility to irritant-induced acute lung injury in mice

Am J Physiol Lung Cell Mol Physiol

Quantitative trait locus analysis of nickel-induced acute lung injury in mice

Am J Respir Cell Mol Biol

Ozone-induced acute lung injury: genetic analysis of F2 mice generated from A/J and C57BL/6J strains

Am J Physiol Lung Cell Mol Physiol

Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

Nat Genet

Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results

Nat Genet

The AXB and BXA set of recombinant inbred mouse strains

Mamm Genome

An edited linkage map for the AXB and BXA recombinant inbred mouse strains

Mamm Genome

Strain distribution pattern in AXB and BXA recombinant inbred strains for loci on murine chromosomes 10, 13, 17, and 18

Mamm Genome

Ozone-induced acute lung injury: genetic analysis of F₂ mice generated from A/J and C57BL/6J strains