Endogenous PGI2 signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model

Endogenous prostaglandin I-2 (PGI(2)) has inhibitory effects on immune responses against pathogens or allergens; however, the immunomodulatory activity of endogenous PGI(2) signaling in endotoxin-induced inflammation is unknown. To test the hypothesis that endogenous PGI(2) down-regulates endotoxin-induced lung inflammation, C57BL/6 wild type (WT) and PGI(2) receptor (IP) KO mice were challenged intranasally with LPS. Urine 6-keto-PGFi., a stable metabolite of PGI(2), was significantly increased following the LPS-challenge, suggesting that endogenous PGI(2) signaling modulates the host response to LPS-challenge. IPKO mice had a significant increase in neutrophils in the BAL fluid as well as increased proteins of KC, LIX, and TNF-alpha in lung homogenates compared with WT mice. In contrast, IL-10 was decreased in LPS-challenged IPKO mice compared with WT mice. The PGI(2) analog cicaprost significantly decreased LPS-induced KC, and TNF-alpha, but increased IL-10 and AREG in bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMs) compared with vehicle-treatment. These results indicated that endogenous PGI(2) signaling attenuated neutrophilic lung inflammation through the reduced inflammatory cytokine and chemokine and enhanced IL-10.