| First Author | Fielhaber JA | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 9 | Pages | 4535-42 |
| PubMed ID | 22450807 | Mgi Jnum | J:188464 |
| Mgi Id | MGI:5440576 | Doi | 10.4049/jimmunol.1003655 |
| Citation | Fielhaber JA, et al. (2012) Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis. J Immunol 188(9):4535-42 |
| abstractText | Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-kappaB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN-beta and STAT1-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STAT1-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STAT1-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase-3). LPS-induced lung injury was attenuated in STAT1 knockout mice. In addition, LPS and IFN-beta-induced apoptosis was absent in cultured cells lacking STAT1, and, unlike in wild-type cells, a permissive effect of rapamycin was not observed. In contrast to its effect on STAT1, rapamycin inhibited NF-kappaB activation in vivo and reduced selected markers of inflammation (i.e., neutrophils in the bronchoalveolar lavage fluid, TNF-alpha). Therefore, although it inhibits NF-kappaB and neutrophilic inflammation, rapamycin augments LPS-induced lung injury and apoptosis in a mechanism that involves STAT1 and the induction of STAT1-dependent apoptosis genes. |
