Novel activation of neutrophil functions

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Title Novel activation of neutrophil functions
Publication Type dissertation
School or College School of Medicine
Department Pathology
Author Feldhaus, Michael John
Contributor Benson, Donelle; Dykstra, Debbie; LI, Wen Lua
Date 1996-08
Description Chronic neutrophil activation results in severe tissue damage leading to loss of limb and life as illustrated from events ranging from adult respiratory distress syndrome (ARDS) to the inflammatory skin lesions associated with Staphylococcal and Streptococcal infections. Conversely, PMNs are critical for host protection, as individuals lacking functional PMNs, in the case of Leukocyte Adhesion Deficiency (LAD), neutropenia, and Chronic Granulomatous Disease (CGD), succumb to persistent bacterial infections. The efficacy of PMNs in host protection derives from their specialized functions. Activation of PMNs upregulates the quantity and affinity of their ?2-integrins with a concomitant loss of L-selectin. The quantitative increase in ?2-integrin upon activation is dependent upon fusion of intracellular granules containing ?2-integrin with the plasma membrane at the site of noxious insult. This also delivers proteases and essential components of the NADPH oxidase complex to the membrane that is necessary for efficient bacterial killing. This dissertation examines novel mechanisms of PMN activation. In the first study neutrophil activation is dissected into two distinct pathways. I demonstrate that sphingomyelinase C (SMC) treatment with the subsequent increase in the intracellular signaling molecule, ceramide, illuminates a bifurcation in PMN activation: ceramide induces degranulation and superoxide generation in the absence of increased ?2-integrin function. SMC induces an increase in ?2-integrin surface expression but, unusually, the integrin is maintained in a low affinity state. This correlates with in vivo data showing SMC mediates dysfunctional PMN sequestration within the vasculature. In the second study I show ICAM-3 engagement by specific epitope-mapped antibodies induces cytoskeletal dependent functional upregulation of the ?2-integrins. Signaling through this adhesion molecule in leukocytes was previously poorly defined. We demonstrate phosphorylation events by PKC and tyrosine kinases of several proteins after engagement, whereas inhibitors of these kinases result in inhibition of the signal emanating from ICAM-3. In the final study, data are presented illustrating that oncostatin M is a proinflammatory cytokine whose effects are mediated through activation of endothelium. In conclusion, these studies illustrate the complex regulation of PMN activation by defining diverse signaling pathways resulting in activation of specific effector functions.
Type Text
Publisher University of Utah
Subject Immunology; Physiology
Subject MESH Inflammation; Neutrophils; Proteins; Endothelial Cells
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Novel activation of neutrophil functions.." Spencer S. Eccles Health Sciences Library. Print version of "Novel activation of neutrophil functions.." available at J. Willard Marriott Library Special Collection. QR6.5 1996 .F44.
Rights Management © Michael John Feldhaus.
Format application/pdf
Format Medium application/pdf
Format Extent 2,489,948 bytes
Identifier undthes,4603
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship Awards from the Nora Eccles Treadwell Foundation and United States Public Health grant RO1 HL 44513, and PO50 HL50153.
Master File Extent 2,490,003 bytes
ARK ark:/87278/s6m32xnk
Setname ir_etd
ID 191949
Reference URL https://collections.lib.utah.edu/ark:/87278/s6m32xnk
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