Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia

Abstract

1 Hydrogen sulfide (H 2 S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H 2 S in the organ injury caused by severe endotoxemia in the rat. 2 Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg À1 intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg À1 i.v.) or DLpropargylglycine (PAG, 10-100 mg kg À1 i.v.), an inhibitor of the H 2 S-synthesizing enzyme cystathionine-g-lyase (CSE). PAG was administered either 30 min prior to or 60 min after the induction of endotoxemia. 3 Endotoxemia resulted in circulatory failure (hypotension and tachycardia) and an increase in serum levels of alanine aminotransferase and aspartate aminotransferase (markers for hepatic injury), lipase (indicator of pancreatic injury) and creatine kinase (indicator of neuromuscular injury). In the liver, endotoxemia induced a significant increase in the myeloperoxidase (MPO) activity, and in the expression and activity of the H 2 S-synthesizing enzymes CSE and cystathionine-b-synthase. 4 Administration of PAG either prior to or after the injection of LPS dose-dependently reduced the hepatocellular, pancreatic and neuromuscular injury caused by endotoxemia, but not the circulatory failure. Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H 2 S and in the liver. 5 These findings support the view that an enhanced formation of H 2 S contributes to the pathophysiology of the organ injury in endotoxemia. We propose that inhibition of H 2 S synthesis may be a useful therapeutic strategy against the organ injury associated with sepsis and shock.

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

“…H 2 S has been proposed as a potential endogenous ligand for K ATP channels and induces K ATP channel-mediated vasorelaxation [28] in several vascular tissues, promoting speculation that H 2 S may play a role in endotoxic shock, an important form of acute inflammation, as mentioned. Indeed, early studies using cecal ligation and puncture (CLP) or injection of bacterial LPS into rats or mice significantly increased the expression of CSE and CBS and H 2 S synthesis in plasma, vascular tissues, lung, liver, kidney and pancreas [21,[29][30][31][32]. This suggested that, as with • NO synthesis (via inducible nitric oxide synthase [iNOS]), H 2 S synthesis is also an inducible phenomenon.…”

“…Conversely, administration of the CSE inhibitor propargylglycine (PAG; see later) to LPS-or CLPtreated animals decreased plasma H 2 S levels significantly, tissue edema and increased survival [21,29,30], suggesting that elevated plasma H 2 S was likely to be associated with the hemodynamic collapse observed in septic shock [21]. It should be noted that the protective effects of PAG may be independent of the improvement of hemodynamics (or CSE), since PAG treatment alone did not alter systemic blood pressure or affect LPS-induced hypotension but did significantly reduce the hepatic, pancreatic and neuromuscular damage induced by LPS [31]. In hemorrhagic shock however, blood withdrawal led to significantly increased liver (but not kidney) and plasma levels of H 2 S, and pretreatment of rats with PAG or b-cyanoalanine (BCA; a reversible inhibitor of CSE) reduced liver H 2 S synthesis and partially restored systemic blood pressure [20,35].…”

“…• NO synthesis) [21,[29][30][31]. Similarly, pretreatment of rats with PAG for 1 h prior to blood withdrawal was also protective as PAG increased heart rate recovery time, significantly reduced liver, lung and plasma levels of TNF-a and IL-6 and, in the liver, PAG reduced neutrophilic accumulation and tissue damage [35].…”

Hydrogen Sulfide Is an Endogenous Potentiator of T Cell Activation

“…3), metabolic hibernation (4,5), protection from ischemia/reperfusion injury (6 -10), oxygen sensing (11), vasodilatation (12,13), and promotion of angiogenesis (14). In common with nitric oxide, H 2 S is also implicated as both a pro- (15)(16)(17)(18) and antiinflammatory (18 -21) molecule in innate immune cells. Although the role of H 2 S signaling has been characterized in many other tissues and systems, it is unclear what role it plays in the regulation of the adaptive immune system.…”

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

“…12 Besides, experimental data in animals show that an enhanced production of endogenous H 2 S contributes to the pathophysiology of the organ injury associated with sepsis and shock. 13,14 Pharmacological effects of H 2 S are essentially related to two distinct mechanisms: first, the ability to activate/open membrane K ATP channels 7 and second, and the modulation of gene transcription by the activation of different signaling pathways. Many studies, focused on myocardial protection, have shown the cardioprotective effects of H 2 S in in vitro and in vivo experiments.…”