A blockade of complement activation prevents rapid intestinal ischaemia-reperfusion injury by modulating mucosal mast cell degranulation in rats.
We attempted to define the putative role of complement activation in association with mucosal mast cell (MMC) degranulation in the pathogenesis of rapid intestinal ischaemia-reperfusion (I/R) injury. We prepared complement activity-depleted rats by the administration of the anti-complement agent K-76COOH and the serine-protease inhibitor FUT-175. Autoperfused segments of the jejunum were exposed to 60 min of ischaemia, followed by reperfusion for various time periods, and the epithelial permeability was assessed by the 51Cr-EDTA clearance rate. The number of MMC was immunohistochemically assessed. In control rats, the maximal increase in mucosal permeability was achieved by 30-45 min of reperfusion. This increase was significantly attenuated by the administration of either K-76COONa alone or in combination with FUT-175. In contrast, the administration of carboxypeptidase inhibitor (CPI), which prevents the inactivation of complement-derived anaphylatoxins such as C5a, significantly enhanced the increase in I/R-induced mucosal permeability. These findings were confirmed morphologically by light microscopy and scanning electron microscopy. In addition, the I/R-induced mucosal injury was accompanied by a marked decrease in the number of MMC, and administration of K-76COOH significantly inhibited this change. These results indicate that complement activation and the generation of complement-derived anaphylatoxins are key events in I/R-induced mucosal injury. It is likely that intestinal I/R-induced mucosal injury may be partially mediated by MMC activation associated with the complement activation.
Kimura
T
T
Department of Internal Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu, Japan.
Andoh
A
A
Fujiyama
Y
Y
Saotome
T
T
Bamba
T
T
D000706:Anaphylatoxins / Q000494:pharmacology; D000818:Animals; D001550:Benzamidines; D015550:Cell Degranulation / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002614:Chelating Agents / Q000493:pharmacokinetics; D002860:Chromium Radioisotopes; D003167:Complement Activation / Q000187:drug effects* / Q000502:physiology*; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D004492:Edetic Acid / Q000493:pharmacokinetics; D006146:Guanidines / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism; D007511:Ischemia / Q000150:complications; D007583:Jejunum / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000627:therapeutic use*
D000706:Anaphylatoxins; D001550:Benzamidines; D002614:Chelating Agents; D002860:Chromium Radioisotopes; D003169:Complement Inactivator Proteins; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid; D004492:Edetic Acid; C032855:nafamostat