Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation.

Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Research Abstract Details 

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Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Abstract Text:

Megan N Ballinger,David M Aronoff,Tracy R McMillan,Kenneth R Cooke,Krystyna Olkiewicz,Galen B Toews,Marc Peters-Golden,Bethany B Moore,

The success of bone marrow transplantation (BMT) as a therapy for malignant and inherited disorders is limited by infectious complications. We previously demonstrated syngeneic BMT mice are more susceptible to Pseudomonas aeruginosa pneumonia due to defects in the ability of donor-derived alveolar macrophages (AMs), but not polymorphonuclear leukocytes (PMNs), to phagocytose bacteria. We now demonstrate that both donor-derived AMs and PMNs display bacterial killing defects post-BMT. PGE2 is a lipid mediator with potent immunosuppressive effects against antimicrobial functions. We hypothesize that enhanced PGE2 production post-BMT impairs host defense. We demonstrate that lung homogenates from BMT mice contain 2.8-fold more PGE2 than control mice, and alveolar epithelial cells (2.7-fold), AMs (125-fold), and PMNs (10-fold) from BMT animals all overproduce PGE2. AMs also produce increased prostacyclin (PGI2) post-BMT. Interestingly, the E prostanoid (EP) receptors EP2 and EP4 are elevated on donor-derived phagocytes post-BMT. Blocking PGE2 synthesis with indomethacin overcame the phagocytic and killing defects of BMT AMs and the killing defects of BMT PMNs in vitro. The effect of indomethacin on AM phagocytosis could be mimicked by an EP2 antagonist, AH-6809, and exogenous addition of PGE2 reversed the beneficial effects of indomethacin in vitro. Importantly, in vivo treatment with indomethacin reduced PGE2 levels in lung homogenates and restored in vivo bacterial clearance from the lung and blood in BMT mice. Genetic reduction of cyclooxygenase-2 in BMT mice also had similar effects. These data clearly demonstrate that overproduction of PGE2 post-BMT is a critical factor determining impaired host defense against pathogens.

Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Publishing Authors By Initials

MN Ballinger,DM Aronoff,TR McMillan,KR Cooke,K Olkiewicz,GB Toews,M Peters-Golden,BB Moore,

For similar genetic processes: gene expression regulation: up-regulation research abstracts see: genetic processes: gene expression regulation: up-regulation research

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Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of immunology (Baltimore, Md. : 1950)

VOLUME: 177

Page Numbers: 5499-508

Journal Abbreviation: J. Immunol.

ISSN: 0022-1767

DAY: 15

MONTH: Oct

YEAR: 2006

Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985117

Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Keywords Mesh Terms:

KEYWORDS: Up-Regulation

MESH TERMS: genetics

Chemical & Substance for Abstract: Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Information

Substance Name: Cyclooxygenase 2

Registry Number: EC 1.14.99.1

Grant and Affiliation Information for Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation.

AFFILIATION: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI 48109-2200, USA.

Country: United States

AGENCY: United States CSR

GRANT: RG8909N

ACRONYM: RG

MEDLINETA: J Immunol

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