SUMMARYCardiac surgery with cardiopulmonary bypass (CPB) leads to a systemic inflammatory response with secretion of cytokines (e.g. IL-6, TNF-a , IL-1b and sIL-2R). The objective of the following study was to investigate in vitro and in vivo cytokine responses and white blood cell counts (WBC) of patients with high versus low cytokine secretion after a coronary artery bypass grafting (CABG) procedure. Twenty male patients undergoing elective CABG surgery with CPB under general anaesthesia were enrolled in the study. On the day of surgery (postoperatively), serum levels of TNF-a and IL-1b were significantly higher in patients of the high IL-6 level group compared to the respective values in the patient group with low IL-6 levels. The inter-individual differences in IL-6 release in patients undergoing CABG surgery with CPB were accompanied by differences in the release of other cytokines, such as TNF-a , IL-1b and sIL-2R. To understand whether genetic background plays a role in influencing cytokine plasma levels under surgical stress, we examined the distribution of polymorphic elements within the promoter regions of the TNF-a and IL-6 genes, and determined their genotype regarding the BAT2 gene and TNF-b intron polymorphisms. Our preliminary data suggests that regulatory polymorphisms in or near the TNF locus, more precisely the allele set 140/150 of the BAT2 microsatellite marker combined with the G allele at 2308 of the TNF-a gene, could be one of the genetic constructions providing for a less sensitive response to various stimuli. Our results suggest: (1) close relationships between cytokine release in the postoperative period, and (2) inter-individually varying patterns of cytokine release in patients undergoing CABG surgery with CPB.

Fibulin-6, a fibroblast-released ECM protein, may play an important role during MR by imparting an effect on CF migration in close and complementary interplay with TGF-β1 signalling.

Fibulin-6, an essential component of extracellular matrix determines the architecture of cellular junctions in tissues undergoing strain. Increased expression and deposition of fibulin-6 facilitates fibroblast migration in response to TGF-β, following myocardial infarction in mouse heart. The underlying mechanism still remains elusive. In conjunction with our previous study, we have now demonstrated that in fibulin-6 knockdown (KD) fibroblasts, not only TGF-β dependent migration, but also stress fiber formation, cellular networking and subsequently fibroblast wound contraction is almost abrogated. SMAD dependent TGF-β pathway shows ~75% decreased translocation of R-SMAD and co-SMAD into the nucleus upon fibulin-6 KD. Consequently, SMAD dependent pro-fibrotic gene expression is considerably down regulated to basal levels both in mRNA and protein. Also, investigating the non-SMAD pathways we observed a constitutive increase in pERK-levels in fibulin-6 KD fibroblast compared to control, but no change was seen in pAKT. Immunoprecipitation studies revealed 60% reduced interaction of TGF-β receptor II and I (TGFRII and I) accompanied by diminished phosphorylation of TGFRI at serin165 in fibulin-6 KD cells. In conclusion, fibulin-6 plays an important role in regulating TGF-β mediated responses, by modulating TGF-β receptor dimerization and activation to further trigger downstream pathways.

Cardiovascular diseases continue to be the most imminent health care problems in the western world, accounting for numerous deaths per year. Heart failure (HF), namely the reduction of left ventricular function, is one of the major cardiovascular disease entities. It is chronically progressing with relapsing acute decompensations and an overall grave prognosis that is little different if not worse than most malignant diseases. Interestingly acute metabolically and/or immunologically challenging events like infections or major surgical procedures will cause relapses in the course of preexisting chronic heart failure, decrease the patients wellbeing and worsen myocardial function. HF itself and or its progression has been demonstrated to be driven at least in part by inflammatory pathways that are similarly turned on by infectious or non-infectious stress responses. These thus add to HF progression or relapse. TNF-α plasma levels are associated with disease severity and progression in HF. In addition, several cytokines (e.g., IL-1β, IL-6) are involved in deteriorating left ventricular function. Those observations are based on clinical studies using inhibitors of cytokines or their receptors or they stem from animal studies examining the effect of cytokine mediated inflammation on myocardial remodeling in models of heart failure. This short review summarizes the known underlying immunological processes that are shared by and drive all: chronic heart failure, select infectious diseases, and inflammatory stress responses. In conclusion the text provides a brief summary of the current development in immunomodulatory therapies for HF and their overlap with treatments of other disease entities.

No abstract