Control of septic inflammation and lung microvascular endothelial barrier by cell junction signaling nexus

Sepsis remains a major cause of morbidity and mortality. Typically, 50% of all sepsis cases start
as an infection in the lungs leading to uncontrolled inflammation and breach of vascular barrier.
These processes directly involve vascular endothelial cells. Despite the recent progress towards
understanding of the basis of pathogen-induced vascular permeability and inflammation,
incomplete understanding of intrinsic mechanisms driving recovery of microvascular integrity
and organ function, represents a critical barrier to progress beyond the problem of ALI and
sepsis. Therefore, further studies identifying specific mechanisms potential interventions
accelerating vascular endothelial cell (EC) barrier restoration after inflammatory insults are
much needed. This translational research study will test a new hypothetical mechanism of Ras-
proximate-1 (Rap1) GTPase-assisted vascular recovery in the models of bacterial lung injury.
We hypothesize that Rap1-induces re-assembly of lung microvascular EC cell junctions and
recruitment of cell junction-associated coiled-coil protein (JACOP). This process stimulates
JACOP interaction with RhoA GTPase-specific guanine nucleotide exchange factor GEF-H1,
leading to inhibition of GEF-H1 activity, and attenuation of RhoA pathway of EC barrier
disruption and inflammation. Based on this mechanism, we will determine JACOP domains with
GEF-H1 inhibitory and cell junction targeting activities and test their efficacy in suppressing the
local endothelial hyper-permeability and inflammation caused by Staphylococcus aureus
bacterial particles. The proposed study may have a broader impact on the other aspects of
vascular responses to inflammatory or pro-angiogenic stimuli mediated by cell adhesive
structures (i.e. adhesion and transmigration of leukocytes, formation of atherosclerotic plaque,
EC barrier compromise and inflammatory injury during cardiac ischemia/reperfusion, etc.).
Characterization of a new Rap1-dependent mechanism of local Rho control by GEF-H1 -
JACOP axis will enhance understanding of feedback mechanisms driving lung self-recovery and
advance development of future therapeutic treatments.

Grant Number: 5R01HL152761-04
NIH Institute/Center: NIH
Principal Investigator: Anna Birukova