RUcore: Rutgers University Community Repository
Mechanisms mediating macrophage activation during acetaminophen-induced hepatotoxicity
Descriptive
TitleInfo
Title
Mechanisms mediating macrophage activation during acetaminophen-induced hepatotoxicity
SubTitle
role of high mobility group box-1 and galectin-3
Name
(type = personal)
NamePart
(type = family)
Dragomir
NamePart
(type = given)
Ana-Cristina
NamePart
(type = date)
1981-
DisplayForm
ANA-CRISTINA DRAGOMIR
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Laskin
NamePart
(type = given)
Debra L
DisplayForm
Debra L Laskin
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Laskin
NamePart
(type = given)
Jeffrey D
DisplayForm
Jeffrey D Laskin
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
GOW
NamePart
(type = given)
ANDREW
DisplayForm
ANDREW GOW
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
GERECKE
NamePart
(type = given)
DEONALD
DisplayForm
DEONALD GERECKE
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
HALL
NamePart
(type = given)
LEROY B
DisplayForm
LEROY B HALL
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2012
DateOther
(qualifier = exact);
(type = degree)
2012-10
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
Classically and alternatively activated macrophages and inflammatory mediators they release play a key role in the pathogenesis of acetaminophen (APAP)-induced hepatotoxicity. In the present studies, we investigated the role of the DNA-binding protein, high mobility group box-1 (HMGB1), and the β-galactoside binding lectin, galectin-3 (Gal-3), in regulating the phenotype of activated macrophages in the liver following APAP intoxication. Culture medium collected from hepatocytes treated for 24 h with 5 mM APAP (CM-AA) stimulated macrophage production of reactive oxygen species and upregulated expression of the antioxidant enzymes catalase and heme oxygenase-1 (HO-1). CM-AA also upregulated expression of the proinflammatory chemokines MIP-1α (CCL3) and MIP-2 (CXCL2), and the eicosanoid biosynthetic enzymes, COX-2 and 12/15-LOX, effects dependent on the p44/42 MAP kinase. Treatment of hepatocytes with ethyl pyruvate (EP) prior to APAP blunted the effects of CM-AA on macrophage ROS production, expression of antioxidant proteins, and COX-2, suggesting that part of the activity in CM-AA was HMGB1. Further studies demonstrated that APAP-induced hepatotoxicity was associated with upregulation of Gal-3 mRNA and protein expression. Loss of Gal-3 resulted in reduced hepatotoxicity in response to APAP. This correlated with decreases in APAP-induced expression of the inflammatory proteins lipocalin 2 (24p3), inducible nitric oxide synthase (iNOS), interleukin-12 (IL-12), tumor necrosis factor- (TNF-), macrophage inflammatory protein-3 (MIP-3α), CD98, the macrophage Gal-3 receptor, and TNF-α receptor 1 (TNFR1). In contrast, APAP-induced expression of the alternative activation markers Ym1 and Fizz-1, as well as tissue repair, was increased in Gal-3-/- mice. These results suggest that Gal-3 contributes to inflammatory mediator production and hepatotoxicity after APAP. We next investigated the role of Gal-3 in regulating macrophage proinflammatory phenotype. Following APAP intoxication, increased numbers of proinflammatory CD11b+/Ly6Chi macrophages accumulated in necrotic regions of the liver. These cells were distinct from resident Kupffer cells and expressed Gal-3. Loss of Gal-3 resulted in reduced accumulation of CD11b+/Ly6Chi macrophages in response to APAP and increased accumulation of anti-inflammatory CD11b+/Ly6Clo macrophages. These results suggest that Gal-3 promotes a proinflammatory, classically activated macrophage phenotype in the liver during APAP-induced hepatotoxicity. Taken together, these studies indicate that multiple mechanisms contribute to proinflammatory macrophage activation following APAP intoxication.
Subject
(authority = RUETD)
Topic
Toxicology
Subject
(authority = ETD-LCSH)
Topic
Acetaminophen--Toxicology
RelatedItem
(type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
Identifier
ETD_4291
PhysicalDescription
Form
(authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xix, 186 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = vita)
Includes vita
Note
(type = statement of responsibility)
by Ana-Cristina Dragomir
Subject
(authority = ETD-LCSH)
Topic
Macrophages--Activation
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000066724
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Location
PhysicalLocation
(authority = marcorg);
(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3XW4HM7
Genre
(authority = ExL-Esploro)
ETD doctoral
Back to the top
Rights
RightsDeclaration
(ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
DRAGOMIR
GivenName
ANA-CRISTINA
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2012-09-26 09:40:35
AssociatedEntity
Name
ANA-CRISTINA DRAGOMIR
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2012-10-31
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = end)
2013-10-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2013.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
Back to the top
Technical
FileSize
(UNIT = bytes)
2973696
OperatingSystem
(VERSION = 5.1)
windows xp
ContentModel
ETD
MimeType
(TYPE = file)
application/pdf
MimeType
(TYPE = container)
application/x-tar
FileSize
(UNIT = bytes)
2979840
Checksum
(METHOD = SHA1)
7f8d86e2da5170c032a6abb1091b03871bee19ec
Back to the top
Statistical Profile