Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1

• DOI: 10.1016/j.intimp.2014.02.017
• Publication Date: 2014-02-26T14:54:32Z
• Authors: Yun-peng Luo; Lei Jiang; Kai Kang; Dong-sheng Fei; Xiang-lin Meng; Chuan-chuan Nan; Shang-ha Pan; Ming-ran Zhao; Ming-yan Zhao
• Keywords: Male; 0303 health sciences; Inflammasomes; Acute Lung Injury; Caspase 1; Interleukin-1beta; Interleukin-18; NF-kappa B; Membrane Proteins; 3. Good health; CARD Signaling Adaptor Proteins; Mice, Inbred C57BL; 03 medical and health sciences; Malondialdehyde; NLR Family, Pyrin Domain-Containing 3 Protein; Animals; Hemin; RNA, Messenger; Apoptosis Regulatory Proteins; Carrier Proteins; Lung; Heme Oxygenase-1; Peroxidase

NLRP3 inflammasome activation contributes to acute lung injury (ALI), accelerating caspase-1 maturation, and resulting in IL-1β and IL-18 over-production. Heme oxygenase-1 (HO-1) plays a protective role in ALI. This study investigated the effect of hemin (a potent HO-1 inducer) on NLRP3 inflammasome in sepsis-induced ALI. The sepsis model of cecal ligation and puncture (CLP) was used in C57BL6 mice. In vivo induction and suppression of HO-1 were performed by pretreatment with hemin and zinc protoporphyrin IX (ZnPP, a HO-1 competitive inhibitor) respectively. CLP triggered significant pulmonary damage, neutrophil infiltration, increased levels of IL-1β and IL-18, and edema formation in the lung. Hemin pretreatment exerted inhibitory effect on lung injury and attenuated IL-1β and IL-18 secretion in serum and lung tissue. In lung tissues, hemin down-regulated mRNA and protein levels of NLRP3, ASC and caspase-1. Moreover, hemin reduced malondialdehyde and reactive oxygen species production, and inhibited NF-κB and NLRP3 inflammasome activity. Meanwhile, hemin significantly increased HO-1 mRNA and protein expression and HO-1 enzymatic activity. In contrast, no significant differences were observed between the CLP and ZnPP groups. Our study suggests that hemin-inhibited NLRP3 inflammasome activation involved HO-1, reducing IL-1β and IL-18 secretion and limiting the inflammatory response.