title: FK409 inhibits both local and remote organ damage after intestinal ischaemia.
abstract: In addition to localized tissue injury, intestinal ischaemia-reperfusion (I/R) leads to remote organ damage, in particular to the lungs. Given that nitric oxide (NO) can attenuate I/R-induced tissue injury in many situations, this study evaluated the effects of the NO donor, FK409, on leukocyte adhesion in the microcirculation of the intestinal villus and also assessed pulmonary tissue damage after intestinal I/R injury. PVG rats were subjected to 30 min intestinal ischaemia and a sub-group of animals received the NO donor FK409 (10 mg/kg; i.v.) both 30 min prior to ischaemia and 30 min post-reperfusion. The intestinal mucosal surface was visualized via an incision made in an exteriorized ileal segment and leukocyte adhesion in the villous microcirculation was determined by in vivo microscopy. Total and differential leukocyte counts from peripheral blood were evaluated. Lungs were removed at the end for histological assessment. Six out of ten untreated I/R animals failed to survive the 2 h reperfusion period, whereas all ten FK409-treated animals survived. I/R induced a significant increase in villous leukocyte adhesion of untreated I/R animals (p<0.001) and this was significantly decreased by FK409 treatment (p<0.001). The total leukocyte count was significantly decreased in untreated I/R animals (p<0.001) and this primarily resulted from a reduction in circulating neutrophil numbers. This effect was not observed in FK409-treated animals. Collapsed alveoli, thickened interstitial walls, and a dense neutrophilic infiltrate were apparent in the lungs of untreated I/R animals, whereas lung histology was normal in FK409-treated animals. In conclusion, FK409 prevented mortality, significantly reduced villous leukocyte adhesion, maintained circulating leukocyte numbers, and prevented pulmonary tissue injury following intestinal I/R. FK409 may therefore be of value in reducing both local and remote tissue damage and improving outcome in situations where intestinal I/R injury is obligatory, such as small bowel transplantation.
authors.affiliation: Surgical and Anaesthetic Sciences, Division of Clinical Sciences (South), University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK. n.kalia@sheffield.ac.uk
authors.forename: Neena
authors.initials: N
authors.lastname: Kalia
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Kay
authors.initials: K
authors.lastname: Hopkinson
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Stephenson
authors.forename: Richard F M
authors.initials: RF
authors.lastname: Wood
authors.forename: A Graham
authors.initials: AG
authors.lastname: Pockley
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007421:Intestine, Small / Q000098:blood supply*; D007511:Ischemia / Q000473:pathology; D007958:Leukocyte Count; D007962:Leukocytes / Q000502:physiology; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D009574:Nitro Compounds / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D016019:Survival Analysis; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D014665:Vasodilator Agents; C061872:FK 409