Osteopontin deficiency protects against airway remodeling and hyperresponsiveness in chronic asthma.

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 alpha(v)beta3 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.

Angiopoietin-1 protects against airway inflammation and hyperreactivity in asthma.

RATIONALE: The angiopoietins (Ang) comprise a family of growth factors mainly known for their role in blood vessel formation and remodeling. The best-studied member, Ang-1, exhibits antiapoptotic and antiinflammatory effects. Although the involvement of Ang-1 in angiogenesis is well recognized, little information exists about its role in respiratory physiology and disease. On the basis of its ability to inhibit vascular permeability, adhesion molecule expression, and cytokine production, we hypothesized that Ang-1 administration might exert a protective role in asthma. OBJECTIVES: To determine changes in the expression of Ang and to assess the ability of Ang-1 to prevent the histologic, biochemical, and functional changes observed in an animal model of asthma. METHODS: To test our hypothesis, a model of allergic airway disease that develops after ovalbumin (OVA) sensitization and challenge was used. MEASUREMENTS AND MAIN RESULTS: Ang-1 expression was reduced at the mRNA and protein levels in lung tissue of mice sensitized and challenged with OVA, leading to reduced Tie2 phosphorylation. Intranasal Ang-1 treatment prevented the OVA-induced eosinophilic lung infiltration, attenuated the increase in IL-5 and IL-13, and reduced eotaxin and vascular cell adhesion molecule 1 expression. These antiinflammatory actions of Ang-1 coincided with higher levels of IkappaB and decreased nuclear factor-kappaB binding activity. More importantly, Ang-1 reversed the OVA-induced increase in tissue resistance and elastance, improving lung function. CONCLUSIONS: We conclude that Ang-1 levels are decreased in asthma and that administration of Ang-1 might be of therapeutic value because it prevents the increased responsiveness of the airways to constrictors and ameliorates inflammation.