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: 4.11). 02/2009; 41(3):290-6. DOI: 10.1165/rcmb.2008-0307OC
Source: PubMed

ABSTRACT 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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    ABSTRACT: Introduction Obesity and asthma prevalence have been increasing over the past decade. Osteopontin (OPN) is a cytokine, with suggested diverse roles in tissue remodeling, fibrosis, immunomodulation, inflammation, and tumor metastasis. Aim of the work To assess the relation between serum osteopontin, immunoglobulin E (IgE) and body fat percentage in obese and non-obese asthmatic women in addition, to determine whether correlations exist between these parameters and asthma control. Patients and methods This study was conducted on 40 women after taking informed written consents. They were divided into 4 groups (10 each): healthy non-obese non-asthmatic (NO/NA), obese non-asthmatic (O/NA), non-obese asthmatic (NO/A) and obese asthmatic (O/A). All were subjected to full history taking, spirometry to non-asthmatic, asthma control questionnaire (ACQ) to asthmatic, determination of body fat percentage and serum levels of osteopontin and IgE. Results Body fat percentage was positively correlated to serum OPN levels. Body fat percentage was positively correlated to concentrations of IgE. In addition, the correlation between serum OPN levels and serum IgE levels was significantly positive. The improvement (presented by difference between ACQ before and after treatment (Δ ACQ)) was significantly superior in non-obese asthmatic. A negative correlation was detected between Δ ACQ and body fat percentage, serum OPN and IgE concentration. In conclusion Because the multiple roles of OPN action potentially contribute to inflammation in obesity, it is suggested that, in addition to weight reduction, interference with OPN action could become a therapeutic strategy in the treatment of obesity worsening disorders like bronchial asthma.
    01/2013; 63(1). DOI:10.1016/j.ejcdt.2013.10.010
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    ABSTRACT: The aim of this study was to determine the levels of the angiogenic and fibrogenic factors osteopontin (OPN), high-mobility group box-1 (HMGB1), and connective tissue growth factor (CTGF) and the antiangiogenic and antifibrogenic pigment epithelium-derived factor (PEDF) in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and rhegmatogenous retinal detachment with no PVR (RD). Vitreous samples from 48 PDR, 17 PVR and 30 RD patients were studied by enzyme-linked immunosorbent assay. OPN, HMGB1, CTGF, and PEDF levels were significantly higher in PDR patients than in RD patients (P < 0.001; 0.002; <0.001; <0.001, resp.). CTGF and PEDF levels were significantly higher in PVR patients than in RD patients (P < 0.001; 0.004, resp.). Exploratory logistic regression analysis identified significant associations between PDR and high levels of HMGB1, CTGF and PEDF, between PDR with active neovascularization and high levels of CTGF and PEDF, and between PDR with traction retinal detachment and high levels of HMGB1. In patients with PDR, there were significant correlations between the levels of PEDF and the levels of OPN (r = 0.544, P = 0.001), HMGB1 (r = 0.719, P < 0.001), and CTGF (r = 0.715, P < 0.001). In patients with PVR, there were significant correlations between the levels of OPN and the levels of HMGB1 (r = 0.484, P = 0.049) and PEDF (r = 0.559, P = 0.02). Our findings suggest that OPN, HMGB1, and CTGF contribute to the pathogenesis of proliferative vitreoretinal disorders and that increased levels of PEDF may be a response to counterbalance the activity of angiogenic and fibrogenic factors in PDR and PVR.
    Mediators of Inflammation 01/2012; 2012:493043. DOI:10.1155/2012/493043 · 2.42 Impact Factor
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    ABSTRACT: Cerium oxide (CeO₂) represents an important nanomaterial with wide ranging applications. However, little is known regarding how CeO₂ exposure may influence pulmonary or systemic inflammation. Furthermore, how mast cells would influence inflammatory responses to a nanoparticle exposure is unknown. We thus compared pulmonary and cardiovascular responses between C57BL/6 and B6.Cg-Kit(W-sh) mast cell deficient mice following CeO₂ nanoparticle instillation. C57BL/6 mice instilled with CeO₂ exhibited mild pulmonary inflammation. However, B6.Cg-Kit(W-sh) mice did not display a similar degree of inflammation following CeO₂ instillation. Moreover, C57BL/6 mice instilled with CeO₂ exhibited altered aortic vascular responses to adenosine and an increase in myocardial ischemia/reperfusion injury which was absent in B6.Cg-Kit(W-sh) mice. In vitro CeO₂ exposure resulted in increased production of PGD₂, TNF-α, IL-6 and osteopontin by cultured mast cells. These findings demonstrate that CeO₂ nanoparticles activate mast cells contributing to pulmonary inflammation, impairment of vascular relaxation and exacerbation of myocardial ischemia/reperfusion injury.
    Nanotoxicology 11/2010; 5(4):531-45. DOI:10.3109/17435390.2010.530004 · 7.34 Impact Factor