Development of a novel immunomodulatory therapy for cardiac inflammation

Bakgrund:

Immunomodulatory treatments against the damaging cardiac inflammation that occurs in myocardial infarction (MI), myocarditis and sepsis do not currently exist. The alarmin S100A9 is released in large amounts in MI, and also participates in the pathogenesis of myocarditis and sepsis. We have recently shown that blockade of S100A9 with ABR-238901, a small molecule that blocks the interaction with its receptors TLR4 and RAGE, reduces inflammation and improves cardiac function in mice with MI.

In mice with LPS-induced sepsis, ABR-238901 significantly reduced mortality and the systemic levels of inflammatory cytokines and chemokines. Målsättning:

We hypothesise that S100A9 is an early trigger of common immune mechanisms in diseases with a cardio-inflammatory component. Our experimental aim is to characterise these mechanisms and to design treatment strategies aiming to dampen inflammation and improve cardiac function. In the clinical arm, we aim to identify novel soluble mediators for cardiovascular risk evaluation and follow-up in MI and sepsis patients.

Arbetsplan:

We will study the influence of S100A9 blockade on cardiac function, fibrosis and remodelling in animal models of MI, myocarditis and sepsis. The effects on the hematopoietic and myeloid responses, cardiac and systemic inflammation, cardiomyocyte respiratory function and apoptosis will also be assessed. In-vitro, we will examine the activation of inflammatory mechanisms triggered by S100A9 in cardiomyocytes, myeloid cells, endothelial cells and fibroblasts, and we will define the relative role of TLR4 and RAGE and of their downstream signalling pathways.

In parallel, we will attempt to find the optimal treatment strategy for future testing in large animal models and clinical trials.

In the prospective LundHeartGene-MR study of MI patients, we will explore how the dynamics of pro-inflammatory and pro-reparatory mediators in plasma from the acute to the recovery phase correlate with cardiac recovery and prognosis. The relationships between acute S100A9 levels and prognosis will also be prospectively assessed in a cohort of 674 sepsis patients included in the IMPRESSED study.

Betydelse:

An effective therapy against the inflammatory myocardial damage could potentially improve patient morbidity and mortality in MI, myocarditis and sepsis. Development of novel specific markers is needed in order to identify patients that require immunomodulatory therapies and to monitor treatment efficacy.