title: Hydrogen sulfide up-regulates substance P in polymicrobial sepsis-associated lung injury.
abstract: Hydrogen sulfide (H2S) has been shown to induce the activation of neurogenic inflammation especially in normal airways and urinary bladder. However, whether endogenous H2S would regulate sepsis-associated lung inflammation via substance P (SP) and its receptors remains unknown. Therefore, the aim of the study was to investigate the effect of H2S on the pulmonary level of SP in cecal ligation and puncture (CLP)-induced sepsis and its relevance to lung injury. Male Swiss mice or male preprotachykinin-A gene knockout (PPT-A-/-) mice and their wild-type (PPT-A+/+) mice were subjected to CLP-induced sepsis. DL-propargylglycine (50 mg/kg i.p.), an inhibitor of H2S formation was administered either 1 h before or 1 h after the induction of sepsis, while NaHS, an H2S donor, was given at the same time as CLP. L703606, an inhibitor of the neurokinin-1 receptor was given 30 min before CLP. DL-propargylglycine pretreatment or posttreatment significantly decreased the PPT-A gene expression and the production of SP in lung whereas administration of NaHS resulted in a further rise in the pulmonary level of SP in sepsis. PPT-A gene deletion and pretreatment with L703606 prevented H2S from aggravating lung inflammation. In addition, septic mice genetically deficient in PPT-A gene or pretreated with L703606 did not exhibit further increase in lung permeability after injection of NaHS. The present findings show for the first time that in sepsis, H2S up-regulates the generation of SP, which contributes to lung inflammation and lung injury mainly via activation of the neurokinin-1 receptor.
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Huili
authors.initials: H
authors.lastname: Zhang
authors.forename: Akhil
authors.initials: A
authors.lastname: Hegde
authors.forename: Siaw Wei
authors.initials: SW
authors.lastname: Ng
authors.forename: Sharmila
authors.initials: S
authors.lastname: Adhikari
authors.forename: Shabbir M
authors.initials: SM
authors.lastname: Moochhala
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D002432:Cecum / Q000601:surgery; D017353:Gene Deletion; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D008026:Ligation; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics; D011677:Punctures; D011812:Quinuclidines / Q000008:administration & dosage / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*; D013373:Substance P / Q000096:biosynthesis*; D013440:Sulfides / Q000008:administration & dosage; D015320:Tachykinins / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*