title: The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation.
abstract: BACKGROUND
  Resident macrophages within the tunica muscularis are known to play a crucial role in initiating severe inflammation in response to ischemia reperfusion injury after intestinal transplantation contributing to graft dysmotility, bacterial translocation, and possibly, acute rejection. The p38 mitogen-activated protein kinase is a key player in the signaling of proinflammatory cytokine synthesis in macrophages. Therefore, we investigated the effects of CPSI-2364, an apparent macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway in an isogenic intestinal rat transplantation model.
  
  
  METHODS
  Recipient and donor animals were treated perioperatively with CPSI-2364 (1 mg/kg, intravenously) or vehicle solution. Nontransplanted animals served as control. Animals were killed 30 min, 3 hr, and 18 hr after reperfusion.
  
  
  RESULTS
  CPSI-2364 treatment resulted in significantly less leukocyte infiltration and significantly improved graft motor function (18 hr). Messenger RNA expression of proinflammatory cytokines (interleukin 6) and kinetic active mediators (NO) was reduced by CPSI-2364 in the early phase after transplantation. Histologic evaluation revealed the protective effects of CPSI-2364 treatment by a significantly less destruction of mucosal integrity at all time points. Perioperative treatment with CPSI-2364 improves graft motor function through impaired inflammatory responses to ischemia reperfusion injury by inhibition of proinflammatory cytokines and suppression of nitric oxide production in macrophages.
  
  
  CONCLUSIONS
  CPSI-2364 presents as a promising complementary pharmacological approach preventing postoperative dysmotility for clinical intestinal transplantation.
authors.affiliation: Department of Surgery, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
authors.forename: Martin von
authors.initials: Mv
authors.lastname: Websky
authors.forename: Jun
authors.initials: J
authors.lastname: Fujishiro
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ohsawa
authors.forename: Michael
authors.initials: M
authors.lastname: Praktiknjo
authors.forename: Sven
authors.initials: S
authors.lastname: Wehner
authors.forename: Kareem
authors.initials: K
authors.lastname: Abu-Elmagd
authors.forename: Koji
authors.initials: K
authors.lastname: Kitamura
authors.forename: Joerg C
authors.initials: JC
authors.lastname: Kalff
authors.forename: Nico
authors.initials: N
authors.lastname: Schaefer
authors.forename: Thomas
authors.initials: T
authors.lastname: Pech
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000517:prevention & control; D006835:Hydrazones / Q000008:administration & dosage / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007421:Intestine, Small / Q000098:blood supply* / Q000503:physiopathology / Q000637:transplantation*; D008264:Macrophages / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000813:Anilides; D006146:Guanidines
chemical_list: D006835:Hydrazones; D015850:Interleukin-6; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; C097256:semapimod; D000813:Anilides; D006146:Guanidines