| Foreign body giant cell formation is preceded by lamellipodia formation and can be attenuated by inhibition of Rac1 activation. | |
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MedLine Citation:
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PMID: 17556592 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Macrophages that are recruited to the site of implanted biomaterials undergo fusion to form surface-damaging foreign body giant cells. Exposure of peripheral blood monocytes to interleukin-4 can recapitulate the fusion process in vitro. In this study, we used interleukin-4 to induce multinucleation of murine bone marrow-derived macrophages and observed changes in cell shape, including elongation and lamellipodia formation, before fusion. Because cytoskeletal rearrangements are regulated by small GTPases, we examined the effects of inhibitors of Rho kinase (Y-32885) and Rac activation (NSC23766) on fusion. Y-32885 did not prevent cytoskeletal changes or fusion but limited the extent of multinucleation. NSC23766, on the other hand, inhibited lamellipodia formation and fusion in a dose-dependent manner. In addition, we found that in control cells, these changes were preceded by Rac1 activation. However, NSC23766 did not block the uptake of polystyrene microspheres. Likewise, short interfering RNA knockdown of Rac1 limited fusion without limiting phagocytosis. Thus, phagocytosis and fusion can be partially decoupled based on their susceptibility to NSC23766. Furthermore, poly(ethylene-co-vinyl acetate) scaffolds containing NSC23766 attenuated foreign body giant cell formation in vivo. These observations suggest that targeting Rac1 activation could protect biomaterials without compromising the ability of macrophages to perform beneficial phagocytic functions at implantation sites. |
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Authors:
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Steven M Jay; Eleni Skokos; Farah Laiwalla; Marie-Marthe Krady; Themis R Kyriakides |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-06-07 |
Journal Detail:
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Title: The American journal of pathology Volume: 171 ISSN: 0002-9440 ISO Abbreviation: Am. J. Pathol. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-07-27 Completed Date: 2007-09-13 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 632-40 Citation Subset: AIM; IM |
Affiliation:
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Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut 06519, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aminoquinolines
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pharmacokinetics,
pharmacology Animals Bone Marrow Cells / drug effects, metabolism Cell Shape / drug effects Chemokine CCL2 / genetics, metabolism Dose-Response Relationship, Drug Drug Implants Genotype Giant Cells, Foreign-Body / drug effects, metabolism* Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology Interleukin-4 / pharmacology Macrophages / drug effects, metabolism Mice Mice, Inbred C57BL Mice, Knockout Microspheres Monomeric GTP-Binding Proteins / antagonists & inhibitors, genetics, metabolism Phagocytosis / drug effects Pseudopodia / metabolism* Pyrimidines / pharmacokinetics, pharmacology RNA Interference RNA, Small Interfering / genetics rac1 GTP-Binding Protein / antagonists & inhibitors, genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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GM 072194-01/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aminoquinolines; 0/Ccl2 protein, mouse; 0/Chemokine CCL2; 0/Drug Implants; 0/NSC 23766; 0/Pyrimidines; 0/RNA, Small Interfering; 207137-56-2/Interleukin-4; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor; EC 3.6.5.2/Monomeric GTP-Binding Proteins; EC 3.6.5.2/rac1 GTP-Binding Protein |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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