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Identification of distinct macrophage subpopulations during nitrogen mustard-induced lung injury and fibrosis

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TitleInfo
Title
Identification of distinct macrophage subpopulations during nitrogen mustard-induced lung injury and fibrosis
SubTitle
mechanisms of recruitment and activation
Name (type = personal)
NamePart (type = family)
Venosa
NamePart (type = given)
Alessandro
NamePart (type = date)
1985-
DisplayForm
Alessandro Venosa
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Gow
NamePart (type = given)
Andrew J
DisplayForm
Andrew J Gow
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Laskin
NamePart (type = given)
Debra L
DisplayForm
Debra L Laskin
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
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)
Zarbl
NamePart (type = given)
Helmut
DisplayForm
Helmut Zarbl
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Hall
NamePart (type = given)
LeRoy
DisplayForm
LeRoy 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 (encoding = w3cdtf); (qualifier = exact)
2015
DateOther (qualifier = exact); (type = degree)
2015-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2015
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Nitrogen mustard (NM) is an alkylating agent known to cause extensive pulmonary injury progressing to fibrosis. This is accompanied by a persistent infiltration of activated macrophages into the lungs which contribute to the development, progression and resolution of tissue damage. Macrophages are highly plastic cells capable of altering their activation state depending on the surrounding microenvironment. Two major phenotypically distinct subpopulations of macrophages have been identified: proinflammatory/cytotoxic M1 and antiinflammatory/wound repair M2 macrophages. Treatment of rats with NM (0.125 mg/kg) resulted in sequential infiltration of iNOS+ and CD11b+CD43+ M1 proinflammatory/cytotoxic macrophages into the lung 1-3 d after exposure, followed by accumulation of CD68+, CD163+, CD206+, YM-1+, ARG-II+ and CD11b+CD43- M2 macrophages, which were most notable at 28 d. This correlated with acute injury and fibrogenesis. Expression of chemokine receptors involved in recruitment of M1 and M2 bone marrow (CCR2+ and CX3CR1+, respectively) and splenic (ATR-1α+) macrophages was also upregulated. Splenectomy resulted in increased numbers of CCR2+, iNOS+ and CD11b+CD43+ proinflammatory M1 macrophages in the lung 1-7 d post exposure. Conversely CD11b+CD43- M2 antiinflammatory/wound repair macrophage accumulation and gene expression was blunted. These changes in macrophage in the lung correlated with heightened tissue injury and more rapid fibrosis. Early after NM exposure, miRNAs involved in regulating the inflammatory response (miR-125, miR-9) were upregulated in lung macrophages. With time, miRNAs involved in promoting proliferation and fibrosis (let7, miR-21, miR-29) were upregulated. Increased expression of HDAC, which regulate histone activity, as well as H3K9Ac and H3K4TM, were also upregulated early after NM exposure. HDAC inhibition using valproic acid resulted in reduced activation of M1proinflammatory/cytotoxic macrophages and increased activation of M2 antiinflammatory/wound repair macrophages, suggesting a pathway regulating macrophage activity in the lung after NM exposure. Identification of macrophage subpopulations participating in the inflammatory response and understanding the mechanisms regulating their activation and recruitment may lead to more targeted and effective treatment against vesicant-induced pulmonary injury.
Subject (authority = RUETD)
Topic
Toxicology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_6801
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xvi, 190 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Nitrogen mustards
Subject (authority = ETD-LCSH)
Topic
Lungs--Wounds and injuries
Note (type = statement of responsibility)
by Alessandro Venosa
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3125VNV
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Venosa
GivenName
Alessandro
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2015-09-30 16:50:25
AssociatedEntity
Name
Alessandro Venosa
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)
2015-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2016-10-30
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 30th, 2016.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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RULTechMD (ID = TECHNICAL1)
ContentModel
ETD
OperatingSystem (VERSION = 5.1)
windows xp
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