Genetic disruption of fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice

Michelle Vaz, Narsa M. Reddy, Subbiah Rajasekaran, Sekhar P. Reddy, Raja Subbiah

Research output: Contribution to journalArticle

Abstract

The activator protein-1 (AP-1) transcription factor, comprising Jun and Fos family proteins, distinctly regulates various cellular processes, including those involved in inflammation. FOS like antigen 1 (Fra-1), amemberof the Fos family, dimerizes with membersof the Jun family and regulates gene expression in a context-dependent manner. Although respiratory toxicants are known to stimulate the expression of Fra-1 in the lung, whether Fra-1 promotes or decreases susceptibility to the development and progression of toxicant-induced lung disease in vivo is not well established. To determine the role of Fra-1 in LPS-induced acute lung injury and mortality, we administered LPS either intraperitoneally or intratracheally to Fra-1 - sufficient (Fra-1 +/+)and Fra-1 - deficient (Fra-1 Δ/Δ) mice. LPS-induced mortality, lung injury, inflammation, cytokine measurements, and AP-1 and NF-κB activities were then assessed in these mice. Fra-1 Δ/Δ mice showed a greater resistance to LPS-induced mortality than did their Fra-1 +/+ counterparts. Consistent with this result, LPS-induced lung injury and inflammatory responses were markedly lower in Fra- 1 Δ/Δ mice than in Fra-1 +/+ mice. Compared with Fra-1 +/+ mice, Fra-1 Δ/Δ mice showed a reduced influx of neutrophils into the lungs, accompanied by a decreased expression of proinflammatory cytokines in response to treatment with LPS. The decreased inflammatory responses in Fra-1 Δ/Δ mice coincided with diminished and increased levels of NF-κB and c-Jun/AP-1 binding, respectively. These results demonstrate that Fra-1/AP-1 plays a key role in promoting LPS-induced injury and mortality in mice, and they suggest that targeting (i.e., inhibiting) this transcription factor may be a useful approach to dampening the adverse effects of exposure to endotoxins.

Original languageEnglish (US)
Pages (from-to)55-62
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume46
Issue number1
DOIs
StatePublished - Jan 1 2012

Fingerprint

Acute Lung Injury
Transcription Factor AP-1
Endotoxins
Mortality
Transcription Factors
Cytokines
Pulmonary diseases
Gene expression
Lung Injury
Proto-Oncogene Proteins c-jun
Lung
Protein Binding
Lung Diseases
Proteins
Pneumonia
Neutrophils
Inflammation
Gene Expression
Wounds and Injuries

Keywords

  • Acute lung injury
  • Cytokines
  • Fra-1
  • Host defense
  • Inflammation

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Genetic disruption of fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice. / Vaz, Michelle; Reddy, Narsa M.; Rajasekaran, Subbiah; Reddy, Sekhar P.; Subbiah, Raja.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 46, No. 1, 01.01.2012, p. 55-62.

Research output: Contribution to journalArticle

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