Vascular actions of antimicrobial peptides

Detta är en avhandling från Cristina Ciornei, [email protected], Department of Anaesthesiology and Intensive Care, Lund Univerity Hospital, Lund, Sweden

Sammanfattning: The present thesis focuses on the vascular effects of antimicrobial peptides especially mechanisms involving the vasodilator nitric oxide (NO), which is released from the blood vessel wall during inflammatory conditions such as sepsis. Bacterial lipopolysaccharide stimulates the expression of nitric oxide synthase (iNOS), which increases the NO production in vascular tissues or cultured vascular smooth muscle cells (VSMC). We found that bactericidal/permeability-increasing protein (BPI) attenuated the lipopolysaccharide-induced increase in NO production in rat aorta and cultured smooth muscle cells in vitro via suppression of lipopolysaccharide-induced expression of iNOS. The effects of the human endogenous antimicrobial peptide LL-37 on lipopolysaccharide -induced iNOS expression and NO production were studied on rat aortas and rat VSMC. LL-37 reduced the lipopolysaccharide-induced iNOS expression and nitric oxide production but after a longer exposure time it was also found to be cytotoxic. The morphological and biochemical changes induced by LL-37 in cultured rat aortic VSMC were thus further investigated and we found that LL-37 induces programmed cell death (apoptosis), indicating that the use of native LL-37 as a therapeutic agent may be limited. We therefore evaluated the effects of some LL-37 analogs, regarding antimicrobial activity, lipopolysaccharide neutralization and toxicity against human erytrocytes and human VSMC. As truncated analogs of LL-37 were similar to LL-37 concerning antimicrobial and lipopolysaccharide neutralization while being less cytotoxic than LL-37, we conclude that they are potential candidates in the treatment of sepsis.

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