Mechanisms of microvascular endothelial cell injury caused by extracellular histones

Mechanisms of microvascular endothelial cell injury caused by extracellular histones
Abstract
Despite the recent progress towards understanding of the basis of increased vascular permeability and
inflammation caused by circulating vasoactive peptides, lipids, and exogenous agents (bacteria, toxins,
particulate matter), the impact of intracellular compounds released by injured tissues and known as danger-
associated molecular patterns (DAMPs) on severity of ongoing acute respiratory syndrome caused by sepsis
or traumatic injury remain poorly understood, and molecular mechanisms underlying deleterious effects of
DAMPs warrant further investigations. This translational study will investigate effects of nucleus-associated
DAMPs, histones, on vascular endothelial function and test a new hypothetical mechanism by which circulating
histones target lung microvascular endothelium and worsen lung injury. The central hypothesis tested in this
application is that circulating histones elevated during acute lung injury, sepsis, trauma, severe inflammation,
or major surgery target vascular endothelium and contribute to overall vascular dysfunction, organ damage and
mortality. This may be achieved through: 1) histone-induced engagement of scavenger receptor cluster of
differentiation 36 (CD36) leading to propagation of endothelial inflammation and barrier dysfunction; and 2)
CD36-induced activation of death signaling by circulating histones contributing to augmentation of ongoing
endothelial dysfunction and lung injury. The proposed study may have a broader impact on the other aspects
of vascular responses to inflammatory or pro-angiogenic stimuli. Proposed studies will provide mechanistic
insights offering better understanding of factors that define severity of sepsis and trauma. These studies may
lead to identification of molecular targets and developing new therapeutic approaches to mitigate such
deleterious effects of circulating DAMPs.

Grant Number: 5R01HL155051-04
NIH Institute/Center: NIH
Principal Investigator: Anna Birukova