Role of hydrogen sulfide in acute pancreatitis and associated lung injury.
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.
Bhatia
Madhav
M
Department of Pharmacology, National University of Singapore, Faculty of Medicine, Bldg. MD2, 18 Medical Dr., Singapore 117597, Singapore. mbhatia@nus.edu.sg
Wong
Fei Ling
FL
Fu
Di
D
Lau
Hon Yen
HY
Moochhala
Shabbir M
SM
Moore
Philip K
PK
D000208:Acute Disease; D000480:Alkynes / Q000494:pharmacology / Q000627:therapeutic use; D000681:Amylases / Q000097:blood; D000818:Animals; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006862:Hydrogen Sulfide / Q000097:blood / Q000378:metabolism*; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000201:enzymology; D010195:Pancreatitis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D009195:Peroxidase / Q000378:metabolism; D010919:Placebos; D012333:RNA, Messenger / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects
D000480:Alkynes; D004791:Enzyme Inhibitors; D010919:Placebos; D012333:RNA, Messenger; C009055:propargylglycine; D009195:Peroxidase; D000681:Amylases; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D005998:Glycine; D006862:Hydrogen Sulfide