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: Huili Zhang, Akhil Hegde, Siaw Wei Ng, Sharmila Adhikari, Shabbir M Moochhala, Madhav Bhatia
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 6 Pg. 4153-60 (Sep 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17785854 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Neurokinin-1 Receptor Antagonists
• Protein Precursors
• Quinuclidines
• Sulfides
• Tachykinins
• preprotachykinin
• L 703606
• Substance P
• sodium bisulfide
• Hydrogen Sulfide

Topics

• Animals
• Cecum (surgery)
• Gene Deletion
• Hydrogen Sulfide (antagonists & inhibitors, metabolism, pharmacology)
• Inflammation Mediators (antagonists & inhibitors, metabolism, pharmacology)
• Ligation
• Lung (drug effects, metabolism, microbiology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Neurokinin-1 Receptor Antagonists
• Protein Precursors (deficiency, genetics)
• Punctures
• Quinuclidines (administration & dosage, therapeutic use)
• Sepsis (drug therapy, genetics, metabolism, microbiology)
• Substance P (biosynthesis)
• Sulfides (administration & dosage)
• Tachykinins (deficiency, genetics)
• Up-Regulation (drug effects)