Role of hydrogen sulfide in acute pancreatitis and associated lung injury

ABSTRACT Hydrogen sulfide (H 2 S) is a naturally occurring gas with potent vasodilator activity. Cystathionine‐γ‐lyase (CSE) and cystathionine‐β‐synthase (CBS) utilize l ‐cysteine as substrate to form H 2 S. Of these two enzymes, cystathionine‐γ‐lyase (CSE) is believed to be the key enzyme that forms H 2 S in the cardiovascular system. Whilst H 2 S 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 H 2 S 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 H 2 S in regulating the severity of pancreatitis and associated lung injury and raise the possibility that H 2 S may exert similar activity in other forms of inflammation.