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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThe focus this article is on a class of leukocyte adhesion molecules, leukocyte \u03b2\u003Csub\u003E2\u003C\/sub\u003E-integrins, among which Mac-1 (aMb2, CD11b\/CD18) is the most common integrin on neutrophils. The leukocyte Mac-1 receptor interacts with the glyocoprotein Iba (GPIba) receptor on platelets, thereby regulating pro-inflammatory and pro-thrombotic bidirectional signals in both inflammatory cells and platelets.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe focus of Dr. Daniel I. Simon\u0027s research at University Hospitals Harrington Heart \u0026amp; Vascular Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA, is on a class of leukocyte adhesion molecules, leukocyte \u03b2\u003Csub\u003E2\u003C\/sub\u003E-integrins, among which Mac-1 (\u03b1\u003Csub\u003EM\u003C\/sub\u003Eb\u003Csub\u003E2\u003C\/sub\u003E, CD11b\/CD18) is the most common integrin on neutrophils. The leukocyte Mac-1 receptor interacts with the glyocoprotein Ib\u03b1 (GPIb\u03b1) receptor on platelets, thereby regulating pro-inflammatory and pro-thrombotic bidirectional signals in both inflammatory cells and platelets. Dr. Simon has centered his research on the structure, function, and signaling of Mac-1, identifying the Mac-1 binding site for GPIb\u03b1 and developing tools to disrupt leukocyte-platelet complexes that promote vascular inflammation.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe repair response following vascular injury is an inflammatory process in which neutrophils and monocytes are rapidly recruited to sites of arterial injury, including stented human blood vessels. Neutrophils appear within hours; monocytes\/macrophages predominate at 7 days. Inflammatory cells are the most abundant cells in the stented human intima for months following injury. The inflammatory cells enter the blood vessel through a 2-step process, involving selectin-mediated rolling and then firm adhesion and diapedesis through the integrin Mac-1.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EInoue et al. [\u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 1996] observed that upregulation of the Mac-1 receptor on neutrophils predicts restenosis risk. Dr. Simon used Mac-1 knockout mice to prove the importance of the receptor in the vascular injury response [Simon DI et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2000]. Following arterial injury, the wild-type mouse (Mac-1+\/+) develops thick neointima while the Mac-1-\/- mouse is protected from neointima growth. In stented rabbit arteries, brisk recruitment of inflammatory cells was disrupted by antibody targeting of the Mac-1 receptor, resulting in dramatically reduced restenosis [Rogers C et al. \u003Cem\u003EProc Natl Acad Sci U S A\u003C\/em\u003E 1998]. In humans, a single nucleotide polymorphism (SNP) in the CD18 locus of the \u03b22 integrin is highly predictive of restenosis following stenting [Koch W et al. \u003Cem\u003EAm J Cardiol\u003C\/em\u003E 2001] (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/3\/17\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022CD 18 Genetic Polymorphism Linked to Restenosis Risk.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1361659824\u0022 data-figure-caption=\u0022CD 18 Genetic Polymorphism Linked to Restenosis Risk.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/3\/17\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/3\/17\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/3\/17\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13986\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003ECD 18 Genetic Polymorphism Linked to Restenosis Risk.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from Elsevier. Koch W et al. Association of a CD18 gene polymorphism with a reduced risk of restenosis after coronary stenting. \u003Cem\u003EAm J Cardiol\u003C\/em\u003E 2001;88(10):1120.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-6\u0022\u003EMac-1 signaling via ligand engagement and clustering is important in amplifying the inflammatory response. Clustering of Mac-1 activates the master inflammatory transcription factor NFkB via a Toll\/IL-1 receptor family-like signaling pathway [Shi et al. \u003Cem\u003ECirculation Research\u003C\/em\u003E 2001]. Mac-1 signaling also regulates the expression of the transcription factor Foxp1 [Shi C et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2004], which serves as a repressor of the gene encoding the M-CSF receptor. Mac-1 signaling downregulates the expression of Foxp1, thereby promoting monocyte differentiation and pro-inflammatory macrophage functions. Overexpression of Foxp1 specifically in monocytes\/macrophages prevents monocyte maturation, resulting in reduced vascular inflammation and atherosclerosis.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe interaction between Mac-1 and platelet GPIb\u03b1 broadly regulates inflammation in diverse animal models, including restenosis, vasculitis, glomerulonephritis, and demyelinating diseases. Dr. Simon is using these model systems to develop anti-inflammatory drugs for this diverse disease subset. Using chimeric integrins, his laboratory identified the 16-amino acid sequence within the I-domain of Mac-1 that is necessary and sufficient for Mac-1 binding to GPIb\u03b1. A peptide (M2) corresponding to this sequence or an antibody targeting this sequence (anti-M2) block Mac-1 binding to GPIb\u03b1 but not to other Mac-1 ligands, including fibrinogen, ICAM-1, and JAM-3. Two of these amino acids, threonine 213 and arginine 216, are critical for binding GPIb\u03b1 [Ehlers R et al. \u003Cem\u003EJ Exp Med\u003C\/em\u003E 2003].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThe first approach to disrupting platelet binding to leukocytes \u003Cem\u003Ein vivo\u003C\/em\u003E was leveraging the anti-M2 antibody. Anti-M2 reduced neointimal thickening 28 days after injury and attenuated tissue injury responses in models of glomerulonephritis [Hirahashi J et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2009]. and demyelinating disease [Langer HF et al. \u003Cem\u003ECirculation Research\u003C\/em\u003E 2012]. These and other studies strongly suggest that virtually all inflammation is platelet-dependent.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EUnderstanding the molecular mechanisms of inflammatory cell recruitment and monocyte differentiation provides insights necessary to develop anti-inflammatory strategies for broadly modulating vascular injury.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/3\/17.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nznek1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznek1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}