Adhesive and signaling mechanisms in abdominal sepsis
Abstract: Sepsis is a major cause of mortality in intensive care units despite decades of scientific efforts. The lung is recognized as the most sensitive and critical organ affected by the hyper-inflammatory response in septic patients. Immune cell dysfunction develops in later phases of sepsis making patients susceptible to infections. The aim of this dissertation was to reveal pro- and anti-inflammatory mechanisms in abdominal sepsis induced by cecal ligation and puncture (CLP). It was found that immunoneutralization of LFA-1 or Mac-1 not only reduced neutrophil infiltration but also protected against sepsis-caused lung damage. We observed that HMG-CoA reductase inhibitor regulates pulmonary accumulation of neutrophils via antagonizing CD40 ligand secretion from platelets and via decreasing CXC chemokine formation in the lung. Moreover, HMG-CoA reductase inhibition maintained CD4 T-cell function in spleen by reducing apoptosis and by improving proliferation as well as by preserving the ability to produce IFN-γ in the spleen. Moreover, inhibition of HMG-CoA reductase decreased sepsis-induced generation of regulatory T-cells. HMG-CoA reductase inhibitor abolished CLP-evoked increase in the plasma levels of HMGB1 and IL-6. In addition, it was noted that NFAT was activated after induction of sepsis, which was found to regulate pulmonary neutrophil recruitment and tissue damage, systemic inflammation, as well as T-cell dysfunction in abdominal sepsis. Thus, these results identify adhesive and signaling mechanisms, which are of particular importance in modulating septic lung injury and immunosuppression. Data from this thesis may pave the way for developing more specific and effective therapies for patients with abdominal sepsis.
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