The role of macrophage migration inhibitory factor in post-infarct inflammation and cardiac remodelling.
Creators: name: White, David Andrew
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Myocardial infarction (MI) is a critical clinical scenario leading to loss of functional myocardium and cardiac dysfunction. Inflammation occurs following MI to begin the healing process. Overt or prolonged inflammation however may lead to complications such as adverse ventricular remodelling, cardiac rupture and heart failure. Preventing adverse remodelling following MI remains a challenge to modern cardiology. Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine mediating innate immunity in infection and disease. Yet the role of MIF in the setting of acute MI has not been investigated. This thesis contains combined experimental and clinical studies investigating the role of MIF in cardiac inflammation and ventricular remodelling following MI. I observed elevated MIF plasma levels at day 1 and day 3 in patients with MI. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured. Elevated production and expression of MIF, interlukin-6 (IL-6) and matrix metallanoproteinase-9 (MMP-9) by PBMCs occurred 3 days but not 1 day, after MI, which was attenuated by anti-MIF interventions. Addition of MIF to cultured PBMCs from healthy subjects stimulated production of these markers hereby amplifying inflammatory responses. Using a MIF deficient mouse model, I demonstrated that MIF knockout lowered mortality due to cardiac rupture as well as the severity of ventricular remodelling and cardiac dysfunction compared to wild type counterparts following MI. Further, MIF deficient mice showed attenuated inflammatory infiltration, gene expression of pro-inflammatory chemokine or cytokines, MMP activity and phosphorylation of p38 mitogen activating protein kinase (MAPK) and c-jun N-terminal kinase post-MI. Migration assays revealed that MIF promotes macrophage chemotaxis following MI via activation of p38 MAPK and NF-B. Differential role of cardiac and inflammatory cell derived MIF was studied by generating two chimeric mice either with cardiac (KOWT) or immune cell MIF deficiency (WTKO). Following MI, KOWT mice had delayed onset of immune cell infiltration together with exacerbated ventricular remodelling and dysfunction. These mice displayed enhanced expression of M1 macrophages and impaired M2 macrophage markers associated with poor healing following MI. In contrast, WTKO mice were protected from cardiac rupture and adverse cardiac remodelling. MIF plasma level is quickly elevated in mice within 15 minutes of ischemia which was conversely associated with a decrease in cardiac MIF content indicating significant cardiac release. Clinical investigations conducted in patients with ST-segment elevated MI (STEMI) revealed rapidly elevated MIF levels in circulation upon admission at the first available sampling. Admission MIF levels correlated with eventually infarct size measured by cardiac magnetic resonance imaging at 3 days and 3 months, respectively, following MI. Whereas, levels of routine cardiac biomarkers such as high sensitive troponin I, creatine kinase, myoglobin and C-reactive protein did not have such correlation. For the first time this thesis comprehensively investigated the role of MIF in post-MI pathophysiology. Rapidly released from the ischemic myocardium, MIF promotes early inflammatory responses particularly circulating immune cells and facilitates macrophage migration. MIF exacerbates severity of systemic and regional inflammatory responses via enhanced cytokine production and MMP activation which contribute to the development of ventricular remodelling and adverse consequences such as cardiac rupture. Anti-MIF interventions inhibited inflammatory infiltration and adverse cardiac remodelling highlighting MIF as a therapeutic target to minimise inflammation associated complications following acute MI. The release of MIF from the ischemic myocardium allows for early prediction of eventual infarct size and likely prognostic evaluation.