title: A small molecule, orally active, alpha4beta1/alpha4beta7 dual antagonist reduces leukocyte infiltration and airway hyper-responsiveness in an experimental model of allergic asthma in Brown Norway rats.
abstract: alpha(4)beta(1) and alpha(4)beta(7) integrins are preferentially expressed on eosinophils and mononuclear leukocytes and play critical roles in their recruitment to inflammatory sites. We investigated the effects of TR14035, a small molecule, alpha(4)beta(1)/alpha(4)beta(7) dual antagonist, in a rat model of allergic asthma. Actively sensitized rats were challenged with aerosol antigen or saline on day 21, and the responses evaluated 24 and 48-h later. TR14035 (3 mg kg(-1), p.o.) was given 1-h before and 4-h after antigen or saline challenge. Airway hyper-responsiveness to intravenous 5-hydroxytryptamine was suppressed in TR14035-treated rats. Eosinophil, mononuclear cell and neutrophil counts, and eosinophil peroxidase and protein content in the bronchoalveolar lavage fluid (BALF) were decreased in TR14035-treated rats. Histological study showed a marked reduction of lung inflammatory lesions by TR14035. At 24-h postchallenge, antigen-induced lung interleukin (IL)-5 mRNA upregulation was suppressed in TR14035-treated rats. By contrast, IL-4 levels in BALF were not significantly affected by TR14035 treatment. IL-4 selectively upregulates vascular cell adhesion molecule-1 (VCAM-1), which is the main endothelial ligand of alpha(4) integrins. Intravital microscopy within the rat mesenteric microcirculation showed that 24-h exposure to 1 microg per rat of IL-4 induced a significant increase in leukocyte rolling flux, adhesion and emigration. These responses were decreased by 48, 100 and 99%, respectively in animals treated with TR14035. In conclusion, TR14035, by acting on alpha(4)beta(1) and alpha(4)beta(7) integrins, is an orally active inhibitor of airway leukocyte recruitment and hyper-responsiveness in animal models with potential interest for the treatment of asthma.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibañez, 15, 46010 Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Sanz
authors.forename: Arantxa
authors.initials: A
authors.lastname: Iranzo
authors.forename: José Luis
authors.initials: JL
authors.lastname: Montesinos
authors.forename: Yafa Naim Abu
authors.initials: YN
authors.lastname: Nabah
authors.forename: José
authors.initials: J
authors.lastname: Alfón
authors.forename: Luis A
authors.initials: LA
authors.lastname: Gómez
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
mesh_terms: D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000494:pharmacology; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008642:Mesenteric Veins / Q000166:cytology / Q000187:drug effects; D010047:Ovalbumin / Q000008:administration & dosage; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D012701:Serotonin
chemical_list: D000485:Allergens; D039041:Integrin alpha4beta1; D016023:Integrins; D015848:Interleukin-5; C459380:N-(2,6-dichlorobenzoyl)-4-(2',6'-bismethoxyphenyl)phenylalanine; D012333:RNA, Messenger; C071777:integrin alpha4beta7; D015847:Interleukin-4; D012701:Serotonin; D010649:Phenylalanine; D010047:Ovalbumin