Role of hydrogen sulfide in acute pancreatitis and associated lung injury

Abstract

Hydrogen sulfide (H2S) is a naturally occurring gas with potent vasodilator activity. Cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS) utilize L-cysteine as substrate to form H2S. Of these two enzymes, cystathionine-gamma-lyase (CSE) is believed to be the key enzyme that forms H2S in the cardiovascular system. Whilst H2S has been reported to relax precontracted rat arteries in vitro and to lower blood pressure in the rat, its effect in an inflammatory condition such as acute pancreatitis has not previously been reported. In this paper, we report the presence of H2S synthesizing enzyme activity and CSE (as determined by mRNA signal) in the pancreas. Also, prophylactic, as well as therapeutic, treatment with the CSE inhibitor, DL-propargylglycine (PAG), significantly reduced the severity of caerulein-induced pancreatitis and associated lung injury, as determined by 1) hyperamylasemia [plasma amylase (U/L) (control, 1204+/-59); prophylactic treatment: placebo, 10635+/-305; PAG, 7904+/-495; therapeutic treatment: placebo, 10427+/-470; PAG, 7811+/-428; P<0.05 PAG c.f. placebo; n=24 animals in each group]; 2) neutrophil sequestration in the pancreas [pancreatic myeloperoxidase oxidase (MPO) activity (fold increase over control) (prophylactic treatment: placebo, 5.78+/-0.63; PAG, 2.97+/-0.39; therapeutic treatment: placebo, 5.48+/-0.52; PAG, 3.03+/-0.47; P<0.05 PAG c.f. placebo; n=24 animals in each group)]; 3) pancreatic acinar cell injury/necrosis; 4) lung MPO activity (fold increase over control) [prophylactic treatment: placebo, 1.99+/-0.16; PAG, 1.34+/-0.14; therapeutic treatment: placebo, 2.03+/-0.12; PAG, 1.41+/-0.97; P<0.05 PAG c.f. placebo; n=24 animals in each group]; and 5) histological evidence of lung injury. These effects of CSE blockade suggest an important proinflammatory role of H2S in regulating the severity of pancreatitis and associated lung injury and raise the possibility that H2S may exert similar activity in other forms of inflammation.

l-Cysteine Inhibits Insulin Release From the Pancreatic β-Cell

“…Changes in the tissue H 2 S contents and activities of H 2 S-producing enzymes have been reported in Down syndrome (29,30) and acute pancreatitis (31). The present findings indicate that L-cysteine potently inhibited insulin release from both mouse islets and MIN6 cells.…”

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

“…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.…”

“…Blockade of CSE activity with PAG is anti-inflammatory Therapeutic and prophylactic administration of PAG (100 mg/kg, intraperitoneal) inhibited cerulein-induced pancreatic inflammation and lung injury [70] Guinea-pig:…”

Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation

“…In the recent literature, H 2 S is becoming recognized as a mediator of physiological and/or pathological processes (1)(2)(3). H 2 S is present in micromolar concentrations in blood (4), and it can be synthesized from L-cysteine (L-Cys), which acts as a substrate for two pyridoxal-5Ј-phosphate-dependent enzymes: cystathionine ␤-synthase (CBS; EC 4.2.1.22) and cystathionine ␥-lyase (CSE; EC 4.4.1.1).…”