Absence of α4 but not β2 integrins restrains development of chronic allergic asthma using mouse genetic models

Objective. Chronic asthma is characterized by ongoing recruitment of inflammatory cells and airway hyperresponsiveness leading to structural airway remodeling. Although alpha 4 beta 1 and beta 2 integrins regulate leukocyte migration in inflammatory diseases and play decisive roles in acute asthma, their role has not been explored under the chronic asthma setting. To extend our earlier studies with alpha 4(Delta/Delta) and beta 2(-/-) mice, which showed that both alpha 4 and beta 2 integrins have nonredundant regulatory roles in acute ovalbumin (OVA)-induced asthma, we explored to what extent these molecular pathways control development of structural airway remodeling in chronic asthma. Materials and Methods. Control, alpha 4(Delta/Delta), and beta 2(-/-) mouse groups, sensitized by intraperitoneal OVA as allergen, received intratracheal OVA periodically over days 8 to 55 to induce a chronic asthma phenotype. Post-OVA assessment of inflammation and pulmonary function (airway hyperresponsiveness), together with airway modeling measured by goblet cell metaplasia, collagen content of lung, and transforming growth factor P I expression in lung homogenates, were evaluated. Results. In contrast to control and beta 2(-/-) mice, alpha 4-(Delta/Delta) mice failed to develop and maintain the composite chronic asthma phenotype evaluated as mentioned and subepithelial collagen content was comparable to baseline. These data indicate that beta 2 integrins, although required for inflammatory migration in acute asthma, are dispensable for structural remodeling in chronic asthma. Conclusion. alpha 4 integrins appear to have a regulatory role in directing transforming growth factor beta-induced collagen deposition and structural alterations in lung architecture likely through interactions of Th2 cells, eosinophils, or mast cells with endothelium, resident airway cells, and/or extracellular matrix. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.