Hill and Ward were the first to report that ischemic myocardial injury can induce activation of the complement cascade in a rat infarct model.7) Pinckard et al.8) also showed that ischemic myocardial necrosis was associated with the release of subcellular membrane constituents that are triggered by the early acting components of the complement cascade (C1, C4, C2 and C3) in patients with an acute myocardial infarction. Yasojima et al.9) demonstrated that complement gene expression was upregulated by ischemia and reperfusion in the rabbit heart. Complement activation was reported to induce neutrophil and monocyte recruitment in the ischemic myocardium.10) Weisman et al.11) reported that infusion of soluble human complement receptor type 1 (sCR1) significantly suppressed post-infarct inflammation and necrosis in a rat model of myocardial ischemia and reperfusion. In spite of promising experimental results, recent clinical trials testing the effects of complement inhibition, in patients with acute myocardial infarction, showed disappointing results. Administration of the human anti-C5 monoclonal antibody pexelizumab, in patients with an acute myocardial infarction, had no effect on infarct size and clinical outcome.12-14)

Meldrum et al.15) demonstrated that H₂O₂ alone induced myocardial TNF-α mediated cardiac injury by a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism. Reactive oxygen intermediates may generate a leukotatic stimulus that includes, complement activation, induction of hemorrhagic shock-induced P-selectin expression, chemokine upregulation and an increase in the endothelial intercellular adhesion molecule (ICAM)-1 ability to bind neutrophils.16-19) The use of the antioxidant enzymes superoxide dismutase and catalase reduced the infarct size in dogs with myocardial ischemia and reperfusion.20) However, there have been some failed studies of antioxidant treatment used to prevent myocardial ischemic injury.21)22) Two clinical studies using recombinant human superoxide dismutase in patients with an acute myocardial infarction undergoing percutaneous coronary intervention or thrombolysis showed no significant improvement of left ventricular function.23)24)

Cytokines can self-amplify through a positive feedback loop targeting the nuclear factor (NF)-κB. Upregulation of TNF-α in the infarct myocardium can upregulate the levels of TNF-α in the neighboring normal myocardium, leading to amplified cytokine effects.3) TNF-α stimulates expression of proinflammatory cytokines, chemokines and adhesion molecules by leukocytes and endothelial cells and regulates extracellular matrix metabolism by reducing collagen synthesis and by enhancing matrix metalloprotease (MMP) activity in cardiac fibroblasts;25) other adhesive cytokines such as monocyte chemoattractant protein (MCP)-1 is also induced in the ischemic and reperfused canine myocardium. Kumar et al.26) suggested a significant role for MCP-1 in monocyte trafficking in reperfused myocardium.

Chemokine upregulation is a noted feature of the postinfarction inflammatory response (Table 1).27) Recent investigators have demonstrated strong induction of several chemokines in the ischemic myocardium supporting their role in leukocyte recruitment.4) MCP-1 upregulation has been demonstrated in a mouse model.28) Frangogiannis reported that a MCP-1 -/- infarct mouse model had decreased mesenger ribonucleic acid (mRNA) expression of the cytokine TNF-α, IL-1β, TGF-β and IL-10 and showed defective macrophage differentiation.27) Induction and release of cytokines such as TNF-α and IL-6 are rapidly released in the central zone during a myocardial infarction; however, they are usually maximal in the border zone.3)29) This robust upregulation may return to baseline levels if the infarction is small, and if the infarction is large and the inflammatory response is excessive, there can be sustained cytokine upregulation, corresponding to a chronic remodeling phase.

TGF-β is a multifunctional cytokine that controls proliferation and cellular differentiation in most cells. TGF-β has been shown to be significantly upregulated in an experimental rat model of myocardial infarction; in addition, TGF-β mRNA and protein was significantly increased at the infarct border zone.39)40) During infarct healing, TGF-β may play a role in the suppression of chemokine and cytokine synthesis and is thought to be a key mediator of the transition from inflammation to fibrosis.41) Lefer et al.42) reported that TGF-β injections reduced myocardial ischemic injury mediated by proinflammatory cytokines such as TNF-α during the inflammatory phase of myocardial healing. Anti-TGF-β treatment before or after coronary artery ligation increased mortality and worsened the left ventricular remodeling in mice with non-reperfused myocardial infarction.43) The inhibition of TGF-β signaling by injection of a TGF-β II receptor resulted in reduction of left ventricular remodeling by modulation of cardiac fibrosis; early TGF-β inhibition increased mortality and left ventricular dilatation.44)45) Youn et al.46) reported that the angiotensin converting enzyme inhibitor and angiotensin receptor blockade resulted in decreased TGF-β mRNA expression after nontransmural infarction in the rat.

However, the exact role of TGF-β signaling in the infarcted and remodeled heart is poorly understood considering the complex and unusual biology of TGF-β (Table 2).47)

There are three IL-1 molecules consisting of IL-1α, IL-β and IL-1 Ra that are specific receptor antagonists.48) Bujak et al.49) demonstrated that IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct and plays an important role in the pathogenesis of remodeling after infarction. IL-10 exerts potent anti-inflammatory effects and modulates MMP expression.50-52) However, Zymek et al.53) and our group reported that IL-10 signaling plays a noncritical role in the suppression of inflammatory mediators, resolution of the inflammatory response and fibrous tissue deposition following myocardial infarction in the mouse. This result may be due to the involvement of multiple overlapping regulatory mechanisms controlling various proinflammatory pathways activated in the infarcted myocardium.

CD44 is a cell surface glycoprotein involved in cell-cell interaction and cell adhesion and migration. CD44-hyaluronan interactions play a role in leukocyte extravasation at the inflammatory site and serves as a key factor in the resolution of inflammation through removal of matrix breakdown products and clearance of apoptotic neutrophils.54-56) Huebener et al.57) tested the role of CD44 in infarct healing and demonstrated that CD44 mRNA levels were significantly induced in the infarcted heart; CD44 null mice showed enhanced and prolonged inflammation in the infarcted heart followed by decreased myofibroblast infiltration, reduced collagen deposition and diminished proliferative activity. Huebener et al.57) concluded that CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response. Thrombospondin (TSP)-1 is an adhesive glycoprotein involved in cell to cell and cell to matrix interaction with potent angiostatic properties; it is a TGF-β activator.58) TSP-1 showed strikingly selective localization in the infarct border zone, and TSP-1 knockout animals had markedly increased macrophage and myofibroblast density in the infarct and in remodeling of noninfarcted myocardial areas, and was more extensive in the postinfarction remodeling than in the wild-type mice. Frangogiannis et al.59) concluded that the selective endogenous expression of TSP-1 at the infarct border zone may serve as a "barrier," limiting expansion of granulation tissue and protecting the noninfarcted myocardium from fibrotic remodeling. Smad is an essential protein component of the TGF-β pathway.60) Hao et al.61) showed that TGF-β mRNA was significantly increased in the infarct scar compared to viable myocardium, and that Cardiac Smad 2, 3 and 4 proteins were significantly increased in the border and scar tissues when compared to viable myocardium. These results indicate that TGF-beta/Smad signaling may be involved in the remodeling of the infarct scar. Optimal cardiac repair requires containment of the inflammation in the infarcted area. Extension of the inflammation into the non-infarcted area could result in expansion of the neutrophil infiltration and worsening of the remodeling. Currently, investigators are testing potential treatment strategies for prevention of the expansion of the inflammatory response into viable myocardium.