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: Julio Cortijo, María-Jesús Sanz, Arantxa Iranzo, José Luis Montesinos, Yafa Naim Abu Nabah, José Alfón, Luis A Gómez, Manuel Merlos, Esteban J Morcillo
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 147 Issue 6 Pg. 661-70 (Mar 2006) ISSN: 0007-1188 [Print] England
• PMID: 16432509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Integrin alpha4beta1
• Integrins
• Interleukin-5
• N-(2,6-dichlorobenzoyl)-4-(2',6'-bismethoxyphenyl)phenylalanine
• RNA, Messenger
• integrin alpha4beta7
• Interleukin-4
• Serotonin
• Phenylalanine
• Ovalbumin

Topics

• Allergens (administration & dosage)
• Animals
• Asthma (chemically induced, pathology, physiopathology, prevention & control)
• Bronchial Hyperreactivity (chemically induced, pathology, prevention & control)
• Bronchial Provocation Tests
• Bronchoalveolar Lavage Fluid (cytology)
• Disease Models, Animal
• Gene Expression Regulation
• Integrin alpha4beta1 (antagonists & inhibitors)
• Integrins (antagonists & inhibitors)
• Interleukin-4 (pharmacology)
• Interleukin-5 (genetics, metabolism)
• Leukocyte Rolling
• Leukocytes (drug effects, physiology)
• Lung (drug effects, pathology)
• Male
• Mesenteric Veins (cytology, drug effects)
• Ovalbumin (administration & dosage)
• Phenylalanine (analogs & derivatives, pharmacology, therapeutic use)
• Pneumonia (chemically induced, pathology, prevention & control)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred BN
• Serotonin