title: Complement C5a inhibition improves late hemodynamic and inflammatory changes in a rat model of nonocclusive mesenteric ischemia.
abstract: BACKGROUND
  Nonocclusive mesenteric ischemia (NOMI) can evolve in a variety of low-flow states. Although the mechanisms leading to NOMI-related intestinal necrosis are largely unknown, circumstantial evidence suggests that excessive vasoconstriction and complement activation both play important roles in this process. Because targeting of the circulatory malfunction of the splanchnic area could be of therapeutic relevance, we set out to investigate the long-term effects of treatment with a complement C5a antagonist in a rat model of partial aortic occlusion (PAO)-induced transient mesenteric hypoperfusion.
  
  
  METHODS
  The mean arterial pressure of the splanchnic area was kept between 30 and 40 mm Hg by 60 minutes of PAO in anesthetized male Sprague-Dawley rats. C5a inhibitor acetyl-peptide-A (AcPepA; 4 mg kg(-1) intravenously) or vehicle administration was initiated at the 45th minute of PAO. After 24 hours, the animals were reanesthetized to record the macrohemodynamics and ileal microcirculation, and plasma and tissue samples were taken for determination of high-mobility group box protein-1 (HMGB-1), endothelin-1, tumor necrosis factor (TNF)-α levels, and small intestinal leukocyte infiltration. Epithelial structural changes were visualized by in vivo confocal laser scanning endomicroscopy.
  
  
  RESULTS
  At 24 hours after PAO, mean arterial pressure, heart rate, and cardiac output were significantly greater, the intestinal intramural microcirculation was significantly impaired, and plasma HMGB-1, endothelin-1, TNF-α levels, the degree of epithelial damage and leukocyte infiltration was increased. The AcPepA treatment moderated the hemodynamic and microcirculatory changes, and decreased inflammatory activation and histologic signs of mucosal damage.
  
  
  CONCLUSIONS
  C5a inhibition ameliorated the potentially harmful local mesenteric hypoperfusion and global long-term inflammatory consequences of PAO. This approach is of promise for use in NOMI-associated situations.
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Dániel
authors.initials: D
authors.lastname: Érces
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Nógrády
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Varga
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Szilárd
authors.initials: S
authors.lastname: Szűcs
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: András Tamás
authors.initials: AT
authors.lastname: Mészáros
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Fischer-Szatmári
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Chun
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
authors.affiliation: Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan.
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Boros
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary. Electronic address: kaszaki.jozsef@med.u-szeged.hu.
authors.forename: József
authors.initials: J
authors.lastname: Kaszaki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D024243:HMGB1 Protein / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007082:Ileum / Q000098:blood supply*; D007249:Inflammation / Q000097:blood* / Q000503:physiopathology; D008297:Male; D065666:Mesenteric Ischemia / Q000188:drug therapy* / Q000473:pathology; D008833:Microcirculation / Q000187:drug effects; D018715:Microscopy, Video; D015999:Multivariate Analysis; D010865:Pilot Projects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014654:Vascular Patency / Q000187:drug effects
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D014409:Tumor Necrosis Factor-alpha; C041833:complement C5a-inhibitors; D012697:Serine Endopeptidases