Abstract Details

Title P2RX7 stimulates Mac-1/ICAM-1-dependent leukocyte-endothelial Adhesion through promotion of Neurovascular Insult during Septic Encephalopathy

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) P9 - Poster Session 9 (5:30 PM-6:30 PM)

Poster/Presentation
Number 13-005

Objective Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. We want to show that inhibition of the brain endothelial P2RX7 signaling pathway significantly reduces the mortality of septic mice. Thus, the P2RX7 signaling pathway can be a novel target for the treatment of SE.

Background Sepsis is initiated by an uncontrolled infection that causes a severe systemic inflammatory response and multisystem organ failure. Septic encephalopathy is a serious complication of sepsis that can lead to cerebral atrophy, cognitive impairment, and even mortality. Vascular inflammation is known to play a role in the acute brain dysfunction associated with sepsis.

Design/Methods Using time-lapse in vivo two-photon laser scanning microscopy, we provided the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels.

Results Our data demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia over activation, reduced brain injury, and consequently doubled the early survival of septic mice.

Conclusions These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during Septic Encephalopathy.

Authors/Disclosures
Muhammad Masood Ahmed, PhD (Pharmacy College, Nishtar Medical University,Multan) PRESENTER	Dr. Ahmed has nothing to disclose.
	No disclosure on file
Shumaila Andleeb, Pharm-D (Faculty of Pharmacy, Bahauddin Zakariya University)	No disclosure on file
	No disclosure on file
	No disclosure on file

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