title: Hydrogen sulfide upregulates cyclooxygenase-2 and prostaglandin E metabolite in sepsis-evoked acute lung injury via transient receptor potential vanilloid type 1 channel activation.
abstract: Hydrogen sulfide (H(2)S) has been shown to promote transient receptor potential vanilloid type 1 (TRPV1)-mediated neurogenic inflammation in sepsis and its associated multiple organ failure, including acute lung injury (ALI). Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)/PGE(2) pathway plays an important role in augmenting inflammatory immune response in sepsis and respiratory diseases. However, the interactions among H(2)S, COX-2, and PGE(2) in inciting sepsis-evoked ALI remain unknown. Therefore, the aim of this study was to investigate whether H(2)S would upregulate COX-2 and work in conjunction with it to instigate ALI in a murine model of polymicrobial sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in male Swiss mice. dl-propargylglycine, an inhibitor of H(2)S formation, was administrated 1 h before or 1 h after CLP, whereas sodium hydrosulfide, an H(2)S donor, was given during CLP. Mice were treated with TRPV1 antagonist capsazepine 30 min before CLP, followed by assessment of lung COX-2 and PGE(2) metabolite (PGEM) levels. Additionally, septic mice were administrated with parecoxib, a selective COX-2 inhibitor, 20 min post-CLP and subjected to ALI and survival analysis. H(2)S augmented COX-2 and PGEM production in sepsis-evoked ALI by a TRPV1 channel-dependent mechanism. COX-2 inhibition with parecoxib attenuated H(2)S-augmented lung PGEM production, neutrophil infiltration, edema, proinflammatory cytokines, chemokines, and adhesion molecules levels, restored lung histoarchitecture, and protected against CLP-induced lethality. The strong anti-inflammatory and antiseptic actions of selective COX-2 inhibitor may provide a potential therapeutic approach for the management of sepsis and sepsis-associated ALI.
authors.affiliation: Immunology Program, Center for Life Sciences, National University of Singapore, 117456 Singapore.
authors.forename: Seah-Fang
authors.initials: SF
authors.lastname: Ang
authors.forename: Selena W S
authors.initials: SW
authors.lastname: Sio
authors.forename: Shabbir M
authors.initials: SM
authors.lastname: Moochhala
authors.forename: Paul A
authors.initials: PA
authors.lastname: MacAry
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002432:Cecum; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008026:Ligation; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D011677:Punctures; D018805:Sepsis / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D006862:Hydrogen Sulfide