| First Author | Vaz M | Year | 2012 |
| Journal | Am J Respir Cell Mol Biol | Volume | 46 |
| Issue | 1 | Pages | 55-62 |
| PubMed ID | 21816965 | Mgi Jnum | J:191912 |
| Mgi Id | MGI:5463550 | Doi | 10.1165/rcmb.2011-0169OC |
| Citation | Vaz M, et al. (2012) Genetic disruption of Fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice. Am J Respir Cell Mol Biol 46(1):55-62 |
| abstractText | 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), a member of the Fos family, dimerizes with members of 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-11(+/+)) and Fra-1-deficient (Fra-1(Delta/Delta)) mice. LPS-induced mortality, lung injury, inflammation, cytokine measurements, and AP-1 and NF-kappaB activities were then assessed in these mice. Fra-1(Delta/Delta) 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(Delta/Delta) mice than in Fra-1(+/+) mice. Compared with Fra-1(+/+) mice, Fra-1(Delta/Delta) 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(Delta/Delta) mice coincided with diminished and increased levels of NF-kappaB 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. |
