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Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischemia/reperfusion
K S Kilgore1, J L Park, E J Tanhehco
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626, USA.
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.
Insights
The membrane attack complex (MAC) drives neutrophil recruitment in heart injury by inducing IL-8. Blocking MAC formation reduces heart damage and inflammation, highlighting MAC
Area of Science:
- Cardiovascular Science
- Immunology
- Complement System Biology
Background:
- Neutrophil accumulation and complement system activation, including the membrane attack complex (MAC), are implicated in myocardial ischemia/reperfusion (I/R) injury.
- While high MAC concentrations cause cell lysis, its role at sublytic concentrations on nucleated cells in vivo is less understood.
- In vitro studies suggest MAC modulates cell function by increasing pro-inflammatory mediators like adhesion molecules and cytokines.
Purpose of the Study:
- To investigate the regulatory role of the MAC in interleukin-8 (IL-8) expression and neutrophil recruitment during myocardial I/R injury.
- To determine if MAC influences neutrophil influx and subsequent myocardial damage in a rabbit model.
Main Methods:
- Utilized C6-deficient (MAC-deficient) and C6-sufficient (control) rabbits subjected to regional myocardial ischemia followed by reperfusion.
- Assessed myocardial infarct size, neutrophil influx, and IL-8 expression using ELISA and immunohistochemistry.
Main Results:
- C6-deficient rabbits exhibited significantly reduced myocardial infarct size compared to C6-sufficient controls.
- A marked decrease in neutrophil infiltration was observed in the infarcted myocardium of C6-deficient animals.
- Reduced neutrophil influx correlated with significantly lower IL-8 expression in C6-deficient rabbits.
Conclusions:
- The MAC plays a crucial role in mediating neutrophil recruitment to the reperfused myocardium.
- MAC induces IL-8 expression locally, which in turn promotes neutrophil influx during myocardial I/R injury.
- Targeting the MAC may represent a therapeutic strategy to mitigate neutrophil-mediated damage in cardiac I/R injury.