Flurbiprofen and HCT1026 protect mice against acute pancreatitis-associated lung injury.
Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Flurbiprofen is a powerful nonsteroidal anti-inflammatory drug (NSAID). However, administration of this drug is associated with severe gastrointestinal side effects. The NO-releasing derivative of flubiprofen (nitroflurbiprofen, HCT1026) has recently been developed by the addition of a nitroxybutyl moiety to the flurbiprofen structure. This modification does not interfere with the anti-inflammatory activity of the drug but markedly reduces its ability to induce gastric injury. The effects of treatment with flurbiprofen and HCT1026 on the severity of pancreatitis and the associated lung injury were investigated in a mouse model. Acute pancreatitis was induced in mice by hourly intraperitoneal injections of cerulein. Flurbiprofen and HCT1026 were administered either 30 min before or 1 h after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury were assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic MPO activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitis-associated lung injury was assessed by neutrophil sequestration in the lungs (lung MPO activity) and by histological examination of lung sections. HCT1026 and flurbiprofen, given prophylactically as well as therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of flurbiprofen as well as HCT1026 as potential treatments for pancreatitis-associated lung injury.
Huang
Jiali
J
Department of Pharmacology and Cardiovascular Biology Research Group, National University of Singapore, Singapore.
Moochhala
Shabbir M
SM
Moore
Philip K
PK
Bhatia
Madhav
M
D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D007249:Inflammation; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; C095631:nitroflurbiprofen; D009569:Nitric Oxide; D005480:Flurbiprofen; D009195:Peroxidase; D000681:Amylases