Osteopontin Induces Airway Remodeling and Lung Fibroblast Activation in a Murine Model of Asthma

Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 02/2009; 41(3):290-6. DOI: 10.1165/rcmb.2008-0307OC
Source: PubMed


Airway remodeling is a central feature of asthma; however, the mechanisms underlying its development have not been fully elucidated. We have demonstrated that osteopontin, an inflammatory cytokine and an extracellular matrix glycoprotein with profibrotic properties, is up-regulated in a murine model of allergen-induced airway remodeling. In the present study, we determined whether osteopontin plays a functional role in airway remodeling. Osteopontin (OPN)-deficient (OPN(-/-)) and wild-type mice were sensitized and exposed to inhaled ovalbumin (OVA) or saline for 5 weeks. Collagen production, peribronchial smooth muscle area, mucus-producing cell number, and bronchoalveolar cell counts were assessed. The functional behavior and phenotype of lung fibroblasts from OVA-treated OPN(-/-) and from wild-type mice were studied using ex vivo cultures. OVA-treated OPN(-/-) mice exhibited reduced lung collagen content, smooth muscle area, mucus-producing cells, and inflammatory cell accumulation as compared with wild-type mice. Reduced matrix metalloproteinase-2 activity and expression of transforming growth factor-beta1 and vascular endothelial growth factor were observed in OVA-treated OPN(-/-) mice. Lung fibroblasts from OVA-treated OPN(-/-) mice showed reduced proliferation, migration, collagen deposition, and alpha-smooth muscle actin expression in comparison with OVA-treated wild-type lung fibroblasts. Thus, OPN is key for the development of allergen-induced airway remodeling in mice. In response to allergen, OPN induces the switching of lung fibroblasts to a pro-fibrogenic myofibroblast phenotype.

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    • "In addition, for the first time, we investigated the impact of AT on the expression of OPN, a cytokine directly involved in the AR by inducing increase in the ASM, and epithelium thickness, and airway fibrosis (Kohan et al., 2009; Simoes et al., 2009). Our results show that AT reversed the OVA-induced expression of OPN at the later time point (15 days). "
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    • "OPN is a phosphorylated acidic arginine-glycine-aspartate (RGD)-containing glycoprotein that exists both as an immobilized ECM component and as a soluble multifunctional proinflammatory cytokine, which play important roles in promoting inflammation [29,30], tissue remodeling, fibrosis [29,31-34], and angiogenesis [35-38]. Many of these effects are mediated by the binding of OPN to CD44 receptors and the surface integrin receptor αvβ3 [35,36,39]. "
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