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

¹ Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Correspondence and requests for reprints should be addressed to Neville Berkman, MBBCh, FRCP, Institute of Pulmonology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem, Israel 91120. E-mail: Neville{at}hadassah.org.il

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-β1 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 –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.

Key Words: airway remodeling • fibroblast • mouse model • myofibroblast • osteopontin