title: Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1.
abstract: 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.
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yun-peng
authors.initials: YP
authors.lastname: Luo
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Dong-sheng
authors.initials: DS
authors.lastname: Fei
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xiang-lin
authors.initials: XL
authors.lastname: Meng
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Chuan-chuan
authors.initials: CC
authors.lastname: Nan
authors.affiliation: The Key Hepatosplenic Surgery Laboratory, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Shang-ha
authors.initials: SH
authors.lastname: Pan
authors.affiliation: Department of Pediatrics, Child's Hospital of Harbin City, Harbin, China.
authors.forename: Ming-ran
authors.initials: MR
authors.lastname: Zhao
authors.affiliation: Department of ICU, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: mingyan1970@126.com.
authors.forename: Ming-yan
authors.initials: MY
authors.lastname: Zhao
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000276:immunology; D006427:Hemin / Q000494:pharmacology*; D058847:Inflammasomes / Q000276:immunology*; D020382:Interleukin-18 / Q000097:blood / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009195:Peroxidase / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology; D018805:Sepsis / Q000150:complications / Q000276:immunology* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008565:Membrane Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D006427:Hemin; D009195:Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020170:Caspase 1
keywords: Acute lung injury; Heme oxygenase-1; NLRP3 inflammasome; Sepsis