title: Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischemia/reperfusion.
abstract: Neutrophil accumulation and activation of the complement system with subsequent deposition of the cytolytic membrane attack complex (MAC) have been implicated in the pathogenesis of myocardial ischemia/reperfusion injury. The MAC, when present in high concentrations, promotes target cell lysis. However, relatively little is known about the potential modulatory role of sublytic concentrations of the MAC on nucleated cell function in vivo. In vitro studies demonstrated that the MAC regulates cell function by promoting the expression of pro-inflammatory mediators, including adhesion molecules and pro-inflammatory cytokines. We examined, using C6-deficient and C6-sufficient rabbits, the regulatory role of the MAC in mediating IL-8 expression and subsequent neutrophil recruitment in the setting of myocardial ischemia/reperfusion injury. C6-deficient and C6-sufficient rabbits were subjected to 30 min of regional myocardial ischemia followed by a period of reperfusion. In addition to a significant reduction in myocardial infarct size in C6-deficient animals, analysis of myocardial tissue demonstrated a decrease in neutrophil influx into the infarcted region. The reduction in neutrophil influx correlated with the decreased expression of the neutrophil chemotactic cytokine IL-8, as determined by ELISA and immunohistochemical analysis. The results derived from this study provide evidence that the MAC has an important function in mediating the recruitment of neutrophils to the reperfused myocardium through the local induction of IL-8.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Kilgore
authors.forename: J L
authors.initials: JL
authors.lastname: Park
authors.forename: E J
authors.initials: EJ
authors.lastname: Tanhehco
authors.forename: E A
authors.initials: EA
authors.lastname: Booth
authors.forename: R M
authors.initials: RM
authors.lastname: Marks
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D002465:Cell Movement; D003183:Complement C6 / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000502:physiology*; D016209:Interleukin-8 / Q000378:metabolism*; D007958:Leukocyte Count; D009203:Myocardial Infarction; D017202:Myocardial Ischemia / Q000097:blood / Q000276:immunology*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits
chemical_list: D003183:Complement C6; D015938:Complement Membrane Attack Complex; D016209:Interleukin-8; D009195:Peroxidase