Research Projects

COMPONENTS: Fibrosis, typically a tissue repair mechanism, plays a key role in the pathophysiology of different cardiovascular diseases (CVDs) including ischemic and non-ischemic stress-induced myocardial injury leading to heart failure (HF) [1,2]. Primarily in ischemic atherosclerosis, the onset of fibrotic repair at post myocardial infarction (MI) stage is inevitable to avoid the rupture of left ventricular wall as regeneration of cardiac tissue is found to be limited after MI-induced death of cardiomyocytes [2,3]. Hence, this replacement fibrosis is apparently beneficial, although scar tissue does not contribute to cardiac contractile force [3,4]. In addition, sustained stress, persistent complications and continuous or atypical activation of repair pathways may lead to progressive fibrosis followed by cardiac hypertrophy and HF [5,6]. GENESIS: The event becomes more critical as this beneficial reparative program is evident due to the poor regenerative property of the cardiac tissue, but the consequence of the episodes increase the probability of poorer outcome with sustained cardiac load leading to reactive fibrosis even in non-infarcted zones [3,7]. Hence, the onset and duration of the process is critical for the pathophysiology of fibrosis-induced CVDs [6,8]. The immune system has been a particular field of interest, as it can regulate not only the physiological processes of inflammation, but also tissue repair and regeneration. However, excessive anti-inflammatory response in the resolution process could lead to pathological fibrosis. Therefore, a tight regulation of the anti-inflammatory response could dictate the outcome whether the inflamed tissue will be replaced by scar tissue or regenerated tissue to restore post injury organ function [9]. HYPOTHESIS, RATIONALE & NOVELTY: According to recent evidence, inflammation-switch is super critical in controlling the process of fibrosis from a beneficial to a progressive and detrimental one. In cardiac tissues, fibrotic remodeling initiated with pro-inflammatory signals from necrotic cardiomyocytes and recruited immune cells after any acute or chronic injury which is followed by an anti-inflammatory pro-fibrotic proliferation phase with collagen secretion from activated myofibroblast. The process culminates with a scar formation and an anti-fibrotic maturation phase. As of now, investigations are focused in explaining the impact of fibrosis severity on different cardiac phenotypes and CVDs. But we lack evidence on the underlying mechanisms elucidating the impaired termination which results in a prolonged progressive fibrosis leading to HF. Hence, we will investigate how the anti-inflammatory immune response controls the pro-fibrotic to anti-fibrotic switch in cardiac fibrosis to develop a future immunotherapeutic target for the controlled termination of the process with an integrated approach considering the intensity, duration and metabolic program of proinflammatory signals.