Casting NETs in the fibrotic heart(FIBRONETx) (FIBRONETx)

Neutrophil hyperactivation has detrimental effects on healthy bystander tissue and thus neutrophils are implicated in many inflammatory disease pathologies.The discovery of neutrophil extracellular traps (NETs) described a novel antibacterial function of neutrophils. NETs are extracellular DNA strands also containing histones and granular enzymes such as neutrophil elastase, with an ability to physically trap and kill both bacteria and fungi. NETosis is an active, specific cell biological process6, and the release of highly charged histones, serine proteases, and myeloperoxidase concentrated on DNA fibers into the extracellular space is injurious. Indeed, aberrant NET production has been implicated in autoimmune disease, cardiovascular disease, thrombosis, and others. There are 3 central starting hypotheses driving this proposed research program, each independently or collectively supported by preliminary evidence in the literature. Hypothesis 1: Release of NETs results in vascular damage and promotes fibrotic remodeling. Hypothesis 2: Cardiac tissue damage promotes additional local NET formation and further leukocyte recruitment. Hypothesis 3: Platelets are crucial drivers of NET formation in thromboinflammation during cardiac injury.