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.

Endogenous Hydrogen Sulfide Regulates Inflammatory Response by Activating the ERK Pathway in Polymicrobial Sepsis

“…15A). Moreover, NaHS has been suggested previously to increase lung microvascular permeability in sepsis (27). As a result, application of H 2 S donor, to some extent, worsened sepsis-associated mortality, although severe and lethal CLP model was used in the present study ( Fig.…”

Hydrogen Sulfide Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite in Sepsis-Evoked Acute Lung Injury via Transient Receptor Potential Vanilloid Type 1 Channel Activation

“…Furthermore, SP incites COX-2 and PGE 2 expression in human colonic epithelial cells and HUVECs through the activation of JAK-STAT (15) and MAPK pathways (17), respectively. Given that endogenous H 2 S was known to upregulate SP in sepsis-induced ALI (47) and to regulate inflammatory response in CLP-induced sepsis by activating the ERK1/2 and NFkB pathways (42), there exists the possibility that H 2 S may contribute to sepsis-evoked ALI via the signal transduction pathway of H 2 S-TRPV1-SP-ERK1/2-NF-kB-COX-2-PGEM. Although the exact mechanistic pathway mediating H 2 S induction of COX-2 remains to be investigated, H 2 S and SP may share a common signaling cascade involving the activation of ERK and NF-kB.…”

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…Nonetheless, as a therapeutic tool, pharmaceutical-grade Na 2 S shows great potential and has been successfully used to prevent and treat myocardial infarction, ischemia-reperfusion injury and endotoxic shock [112,113]. It is Table 2 By sharp contrast, no effect was observed with mesalamine or ADT-OH treatment alone, suggesting protective effects in addition to H 2 S release [111] Male Wistar rats: Carageenan-induced hindpaw edema The study concluded that the additional anti-inflammatory effect of S-diclofenac was due to H 2 S release [134] Male Wistar rats: Trinitrobenzene sulfonic acid-induced colitis [125] Male Swiss albino mice: Cecal ligation and puncture-induced sepsis PPT-A gene expression and substance P levels whereas NaSH increased substance P levels and lung injury [71] Balb/C mice: Acute pancreatitis and associated lung inflammation induced by cerulein…”

“…H 2 S has also been proposed as a novel mediator of neurogenic inflammation. Intraperitoneal injection of NaSH into 'normal' mice induced significant NKR1-dependent, but NKR2-and CGRP-independent, increases in plasma levels of SP and pronounced lung inflammation [70], and in sepsis-induced lung injury [71] and acute pancreatitis [72], H 2 S upregulated plasma levels of SP and aggravated lung inflammation. These effects were blocked by either a selective NK1R antagonist or genetic depletion of PPT-A.…”