| First Author | Reddy AT | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 11 | Pages | 5411-20 |
| PubMed ID | 23105142 | Mgi Jnum | J:190671 |
| Mgi Id | MGI:5449455 | Doi | 10.4049/jimmunol.1201487 |
| Citation | Reddy AT, et al. (2012) Endothelial cell peroxisome proliferator-activated receptor gamma reduces endotoxemic pulmonary inflammation and injury. J Immunol 189(11):5411-20 |
| abstractText | Bacterial endotoxin (LPS)-mediated sepsis involves severe, dysregulated inflammation that injures the lungs and other organs, often fatally. Vascular endothelial cells are both key mediators and targets of LPS-induced inflammatory responses. The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) exerts anti-inflammatory actions in various cells, but it is unknown whether it modulates inflammation through actions within endothelial cells. To determine whether PPARgamma acts within endothelial cells to diminish endotoxemic lung inflammation and injury, we measured inflammatory responses and mediators in mice with endothelial-targeted deletion of PPARgamma. Endothelial cell PPARgamma (ePPARgamma) knockout exacerbated LPS-induced pulmonary inflammation and injury as shown by several measures, including infiltration of inflammatory cells, edema, and production of reactive oxygen species and proinflammatory cytokines, along with upregulation of the LPS receptor TLR4 in lung tissue and increased activation of its downstream signaling pathways. In isolated LPS-stimulated endothelial cells in vitro, absence of PPARgamma enhanced the production of numerous inflammatory markers. We hypothesized that the observed in vivo activity of the ligand-activated ePPARgamma may arise, in part, from nitrated fatty acids (NFAs), a novel class of endogenous PPARgamma ligands. Supporting this idea, we found that treating isolated endothelial cells with physiologically relevant concentrations of the endogenous NFA 10-nitro-oleate reduced LPS-induced expression of a wide range of inflammatory markers in the presence of PPARgamma, but not in its absence, and also inhibited neutrophil mobility in a PPARgamma-dependent manner. Our results demonstrate a key protective role of ePPARgamma against endotoxemic injury and a potential ePPARgamma-mediated anti-inflammatory role for NFAs. |
