Endothelial Cell Peroxisome Proliferator-Activated Receptor γ Reduces Endotoxemic Pulmonary Inflammation and Injury

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 (PPAR gamma) exerts anti-inflammatory actions in various cells, but it is unknown whether it modulates inflammation through actions within endothelial cells. To determine whether PPAR gamma acts within endothelial cells to diminish endotoxemic lung inflammation and injury, we measured inflammatory responses and mediators in mice with endothelial-targeted deletion of PPAR gamma. Endothelial cell PPAR gamma (ePPAR gamma) 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 PPAR gamma enhanced the production of numerous inflammatory markers. We hypothesized that the observed in vivo activity of the ligand-activated ePPAR gamma may arise, in part, from nitrated fatty acids (NFAs), a novel class of endogenous PPAR gamma 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 PPAR gamma, but not in its absence, and also inhibited neutrophil mobility in a PPAR gamma-dependent manner. Our results demonstrate a key protective role of ePPAR gamma against endotoxemic injury and a potential ePPAR gamma-mediated anti-inflammatory role for NFAs. The Journal of Immunology, 2012, 189: 5411-5420.