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Identification of distinct macrophage subpopulations during nitrogen mustard-induced lung injury and fibrosis
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Venosa, Alessandro. Identification of distinct macrophage subpopulations during nitrogen mustard-induced lung injury and fibrosis. Retrieved from https://doi.org/doi:10.7282/T3125VNV

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TitleIdentification of distinct macrophage subpopulations during nitrogen mustard-induced lung injury and fibrosis
NameVenosa, Alessandro (author); Gow, Andrew J (chair); Laskin, Debra L (internal member); Laskin, Jeffrey D (internal member); Zarbl, Helmut (internal member); Hall, LeRoy (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2015
Other Date2015-10 (degree)
SubjectToxicology, Nitrogen mustards, Lungs--Wounds and injuries
Extent1 online resource (xvi, 190 p. : ill.)
DescriptionNitrogen 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.
NotePh.D.
NoteIncludes bibliographical references
Noteby Alessandro Venosa
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/T3125VNV
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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