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Osteopontin Deficiency Protects against Airway Remodeling and Hyperresponsiveness in Chronic Asthma

¹ G.P. Livanos and M. Simou Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens, Medical School, Athens; and ² Cellular Immunology Laboratory, Division of Cell Biology, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Correspondence and requests for reprints should be addressed to Davina C.M. Simoes, Ph.D., Thorax Foundation, 3 Ploutarchou Str, Kolonaki, Athens, Greece 10675. E-mail: davinasimoes{at}yahoo.co.uk

Rationale: Osteopontin (OPN) is a cytokine that is upregulated in epithelial cells and macrophages in the lungs of mice during chronic allergen challenge and airway remodeling and also in lungs of patients with asthma. However, it remains unclear whether OPN has an in vivo effect on lung remodeling in allergic asthma. Based on its ability to induce smooth muscle and fibroblast proliferation and migration we hypothesize that OPN regulates lung remodeling and also affects subsequent airway hyperresponsiveness (AHR).

Objectives: Study the role of OPN in airway remodeling using OPN-knockout (KO) mice and a reversal approach administering recombinant mouse OPN (rOPN) in KO mice before challenge.

Methods: A chronic allergen-challenge model of airway remodeling with OPN KO mice, KO mice treated with rOPN, and human bronchial smooth muscle were used.

Measurements and Main Results: OPN deficiency protected mice against ova-induced AHR, which was associated with lower collagen and mucus production, gob-5 mRNA expression, submucosal cell area infiltration, and proliferation. Administration of rOPN to KO mice, just at the final five allergen challenges, exacerbated AHR and all the remodeling characteristics measured. In addition, rOPN increased the expression of IL-13 and pro–matrix metalloproteinase-9 in the lungs. Moreover, we demonstrated that rOPN induces proliferation of human BSM through binding to its _vβ3 integrin receptor and activation of PI3K/Akt downstream signaling pathway.

Conclusions: We conclude that OPN deficiency protects against remodeling and AHR. Thus our data reveal OPN as a novel therapeutic target for airway remodeling and associated AHR in chronic asthma.

Key Words: osteopontin • human smooth muscle cells • remodeling asthma

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Osteopontin (OPN) is a cytokine that is up-regulated in epithelial cells and macrophages of patients with asthma. Remodeling properties of OPN in various models of fibrosis were associated with induction of fibroblast proliferation and migration. What This Study Adds to the Field OPN absence prevented lung function worsening and remodeling in a model of chronic allergen-induced airway remodeling. Recombinant OPN administration confirmed its profibrotic role, pointing to OPN as a novel therapeutic target in asthma remodeling.

 

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