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Mechanisms of silica exacerbated sys...

Brown, Jared Michael.

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Mechanisms of silica exacerbated systemic autoimmune disease in New Zealand mixed mice.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Mechanisms of silica exacerbated systemic autoimmune disease in New Zealand mixed mice./
Author:	Brown, Jared Michael.
Description:	166 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1829.
Contained By:	Dissertation Abstracts International65-04B.
Subject:	Health Sciences, Toxicology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3129994
ISBN:	049677249X

Mechanisms of silica exacerbated systemic autoimmune disease in New Zealand mixed mice.
Brown, Jared Michael.

Mechanisms of silica exacerbated systemic autoimmune disease in New Zealand mixed mice. - 166 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1829.

Thesis (Ph.D.)--University of Montana, 2004.

Silica exposure has been associated with formation of autoantibodies and development of several autoimmune diseases, however, mechanisms leading to these events are unknown. Therefore, the effect of silica on autoimmune disease progression in autoimmune-prone New Zealand mixed mice was studied. Following silica exposure, NZM mice developed high levels of proteinuria and died prematurely due to immune complex and complement deposition within the glomerulus of the kidney as compared to saline and TiO2 exposed mice. Further, silica exposure resulted in higher levels of autoantibodies to nuclear antigen, specifically histones, than saline or TiO2 exposed mice. These effects were mediated in part by the migration of high numbers of CD4+ T cells and B1a B cells to local lymph nodes as well as the decrease in the number of CD4+CD25+ regulatory T cells. Silica exposure induced a shift in the Th1/Th2 balance in favor of a Th1 response as measured by alterations in immunoglobulin isotypes. The increase in autoantibodies following silica exposure in NZM mice involved autoantibodies which preferentially recognized apoptotic cells. Following silica exposure, alveolar macrophages from NZM mice were shown to have increased gene expression levels of several apoptosis genes. Most prominent was an increase in proapoptotic protein kinase Cdelta in alveolar macrophages from silica exposed NZM mice. Using an in vitro model, PKCdelta was found to mediate apoptosis in silica treated bone marrow derived macrophages. Further, TNF-alpha was found to be chronically elevated in lung lavage fluid possibly adding to the induction of apoptosis. Inhibiting the apoptotic response induced by silica in alveolar macrophages using an inhibitor of PKCdelta in vivo significantly reduced silica exacerbated systemic autoimmune disease. Inhibition of PKCdelta in vivo resulted in decreased proteinuria, kidney disease and anti-histone autoantibodies. These results suggest that silica exposure resulted in apoptosis of alveolar macrophages and by blocking apoptosis through PKCdelta the exacerbation of systemic autoimmune disease in NZM mice was inhibited. These data taken together may provide insights into mechanisms by which xenobiotics induce apoptosis and the role apoptosis may play in the progression of systemic autoimmune disease.

ISBN: 049677249XSubjects--Topical Terms:

1017752
Health Sciences, Toxicology.

Mechanisms of silica exacerbated systemic autoimmune disease in New Zealand mixed mice.
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502 $a Thesis (Ph.D.)--University of Montana, 2004.
520 $a Silica exposure has been associated with formation of autoantibodies and development of several autoimmune diseases, however, mechanisms leading to these events are unknown. Therefore, the effect of silica on autoimmune disease progression in autoimmune-prone New Zealand mixed mice was studied. Following silica exposure, NZM mice developed high levels of proteinuria and died prematurely due to immune complex and complement deposition within the glomerulus of the kidney as compared to saline and TiO2 exposed mice. Further, silica exposure resulted in higher levels of autoantibodies to nuclear antigen, specifically histones, than saline or TiO2 exposed mice. These effects were mediated in part by the migration of high numbers of CD4+ T cells and B1a B cells to local lymph nodes as well as the decrease in the number of CD4+CD25+ regulatory T cells. Silica exposure induced a shift in the Th1/Th2 balance in favor of a Th1 response as measured by alterations in immunoglobulin isotypes. The increase in autoantibodies following silica exposure in NZM mice involved autoantibodies which preferentially recognized apoptotic cells. Following silica exposure, alveolar macrophages from NZM mice were shown to have increased gene expression levels of several apoptosis genes. Most prominent was an increase in proapoptotic protein kinase Cdelta in alveolar macrophages from silica exposed NZM mice. Using an in vitro model, PKCdelta was found to mediate apoptosis in silica treated bone marrow derived macrophages. Further, TNF-alpha was found to be chronically elevated in lung lavage fluid possibly adding to the induction of apoptosis. Inhibiting the apoptotic response induced by silica in alveolar macrophages using an inhibitor of PKCdelta in vivo significantly reduced silica exacerbated systemic autoimmune disease. Inhibition of PKCdelta in vivo resulted in decreased proteinuria, kidney disease and anti-histone autoantibodies. These results suggest that silica exposure resulted in apoptosis of alveolar macrophages and by blocking apoptosis through PKCdelta the exacerbation of systemic autoimmune disease in NZM mice was inhibited. These data taken together may provide insights into mechanisms by which xenobiotics induce apoptosis and the role apoptosis may play in the progression of systemic autoimmune disease.
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