title: VCAM-1 contributes to rapid eosinophil accumulation induced by the chemoattractants PAF and LTB4: evidence for basal expression of functional VCAM-1 in rat skin.
abstract: The aim of the present study was to investigate the role of the adhesion pathway alpha4 integrins/vascular cell adhesion molecule type 1 (VCAM-1) in rapid eosinophil accumulation induced by the chemoattractants PAF and LTB4. For this purpose we have used an in vivo model of local 111In-eosinophil accumulation to quantify eosinophil accumulation induced by intradermal administration of platelet-activating factor (PAF) and leukotriene B4 (LTB4) in rats. Initial experiments carried out over 4 hr demonstrated that intravenous administration of an anti-VCAM-1 monoclonal antibody (mAb; 5F10) or an anti-alpha4 integrin mAb (TA2) caused a significant reduction in PAF- or LTB4-induced 111In-labelled eosinophil accumulation. Time-course experiments demonstrated that the anti-VCAM-1 mAb was effective at suppressing early phases of the 111In-labelled eosinophil accumulation induced by PAF and LTB4 (e.g. within the first 60 min). In contrast, 111In-labelled eosinophil accumulation induced by these chemoattractants was unaffected by the local administration of the transcriptional inhibitor actinomycin D, suggesting a role for basally expressed VCAM-1. Indeed, basal expression of VCAM-1 in rat skin sites was demonstrated by the localization of intravenously administered radiolabelled mAb. The localization of the radiolabelled antibody was not altered in skin sites injected with PAF or LTB4. Finally, the inhibitory effects seen with the anti-VCAM-1 mAb were enhanced when the antibody was co-injected into rats with an anti-intercellular adhesion molecule-1 (ICAM-1) mAb (1A29). The combination of these two mAb also caused a significant inhibition of PAF-induced oedema, as quantified by the local accumulation of 125I-labelled human serum albumin. The results indicate a role for alpha4 integrins/VCAM-1 and ICAM-1, in PAF- and LTB4-induced eosinophil accumulation in vivo and suggest that basally expressed VCAM-1 may have a functional role in rapid accumulation of eosinophils induced by chemoattractants.
authors.affiliation: Applied Pharmacology, Imperial College School of Medicine at the National Heart & Lung Institute, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Davies
authors.forename: K
authors.initials: K
authors.lastname: Larbi
authors.forename: A
authors.initials: A
authors.lastname: Allen
authors.forename: M
authors.initials: M
authors.lastname: Sanz
authors.forename: V B
authors.initials: VB
authors.lastname: Weg
authors.forename: D O
authors.initials: DO
authors.lastname: Haskard
authors.forename: R R
authors.initials: RR
authors.lastname: Lobb
authors.forename: S
authors.initials: S
authors.lastname: Nourshargh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003609:Dactinomycin / Q000494:pharmacology; D004487:Edema / Q000276:immunology; D004804:Eosinophils / Q000276:immunology*; D007124:Immunoenzyme Techniques; D039441:Integrin alpha4; D016023:Integrins / Q000276:immunology; D007975:Leukotriene B4 / Q000276:immunology; D008297:Male; D010972:Platelet Activating Factor / Q000276:immunology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000276:immunology*; D012871:Skin Diseases / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016023:Integrins; D010972:Platelet Activating Factor; D011500:Protein Synthesis Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D003609:Dactinomycin; D007975:Leukotriene B4