Dissertation/Thesis Abstract

The role of platelet glycoprotein Ib-IX in systemic inflammation
by Corken, Adam, Ph.D., University of Arkansas for Medical Sciences, 2014, 222; 3703976
Abstract (Summary)

The mammalian blood platelet is responsible for the surveillance of vascular integrity. Chiefly, platelets monitor for damage to the lining of blood vessels and in the event of an injury activate and aggregate to form a hemostatic plug which limits blood loss. This activity is mediated by the function of the platelet membrane receptor, glycoprotein (GP) Ib-IX complex which detects von Willebrand factor (VWF) at damaged vascular sites. The range of vascular disturbance outcomes influenced by GP Ib-IX is not limited to the status of vessel integrity. GP Ib-IX is also capable of modulating the inflammatory response generated in response to microbial penetration of the circulation (sepsis). Under normal conditions, GP Ib-IX contributes to platelet-neutrophil/monocyte interactions in the blood. Loss of functional GP Ib-IX modeled in the hIL-4R/Ibα strain leads to a significant drop in the percent of the neutrophil and monocyte population associated with platelets (∼25%). The loss of VWF expression has no direct influence on the platelet's ability to interact with leukocytes as wild-type and VWF knockout (KO) samples are indistinguishable. This GP Ib-IX mediated interaction persists under septic conditions modeled by cecal ligation and puncture (CLP) as hIL-4R/Ibα samples on average exhibit reduced platelet-neutrophil/monocyte associations. The ability of platelets to interact with circulating leukocytes significantly influences both the neutrophil and monocyte inflammatory phenotype. Ablation of functional GP Ib-IX induces a change in the distribution of "classical" to "non-classical" monocytes during sepsis. Furthermore it alters the secretion profiles of monocyte derived cytokines and chemokines. Neutrophil expression of the integrin Mac-1 is also affected. Absence of GP Ib-IX leads to significantly elevated surface levels of Mac-1 following the induction of sepsis. This study establishes a GP Ib-IX dependent platelet contribution to the inflammatory response in a model of sepsis. As the understanding of sepsis progression remains incomplete, these findings help to establish a better foundational insight into the pathophysiology of sepsis.

Indexing (document details)
Advisor: Ware, Jerry L.
Commitee: Franco, Aime, Kelly, Thomas, Post, Stephen, Suva, Larry
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 76/09(E), Dissertation Abstracts International
Subjects: Cellular biology, Biochemistry, Immunology
Keywords: Mammalian blood platelets, Platelet glycoprotein ib-ix, Vascular integrity
Publication Number: 3703976
ISBN: 978-1-321-76114-6
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