Role of Cyclooxygenase-2 in Exacerbation of Allergen-Induced Airway Remodeling by Multiwalled Carbon Nanotubes

Abstract

The emergence of nanotechnology has produced a multitude of engineered nanomaterials such as carbon nanotubes (CNTs), and concerns have been raised about their effects on human health, especially for susceptible populations such as individuals with asthma. Multiwalled CNTs (MWCNTs) have been shown to exacerbate ovalbumin (OVA)-induced airway remodeling in mice. Moreover, cyclooxygenase-2 (COX-2) has been described as a protective factor in asthma. We postulated that COX-2-deficient (COX-2 2/2 ) mice would be susceptible to MWCNT-induced exacerbations of allergen-induced airway remodeling, including airway inflammation, fibrosis, and mucus-cell metaplasia (i.e., the formation of goblet cells). Wild-type (WT) or COX-2 2/2 mice were sensitized to OVA to induce allergic airway inflammation before a single dose of MWCNTs (4 mg/kg) delivered to the lungs by oropharyngeal aspiration. MWCNTs significantly increased OVA-induced lung inflammation and mucus-cell metaplasia in COX-2 2/2 mice compared with WT mice. However, airway fibrosis after exposure to allergen and MWCNTs was no different between WT and COX-2 2/2 mice. Concentrations of certain prostanoids (prostaglandin D 2 and thromboxane B 2 ) were enhanced by OVA or MWCNTs in COX-2 2/2 mice. No differences in COX-1 mRNA concentrations were evident between WT and COX-2 2/2 mice treated with OVA and MWCNTs. Interestingly, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13 and IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2 2/2 mice, but not in WT mice. We conclude that exacerbations of allergen-induced airway inflammation and mucus-cell metaplasia by MWCNTs are enhanced by deficiencies in COX-2, and are associated with the activation of a mixed Th1/Th2/Th17 immune response.Keywords: carbon nanotubes; nanoparticles; asthma; inflammation; COX-2 Asthma is a chronic airway disease affecting over 22 million people in the United States, and is characterized by periodic acute bronchospasm, accompanied by chronic airway inflammation and remodeling (1, 2). Airway remodeling involves alterations to the airway epithelium such as mucus-cell hyperplasia and the recruitment and/or activation of fibroblasts with accompanying subepithelial fibrosis, as well as airway smooth muscle cell hypertrophy and hyperplasia (3). The pathogenesis of asthma is exacerbated by a variety of agents such as allergen exposure in sensitized individuals, viral infections, and inhaled irritants (4). Concentrations of airborne particulates have been epidemiologically linked to the incidence and severity of asthma attacks (5). Ultrafine air-pollution particles (i.e., nanoparticles) have been suggested to be the most important in asthma exacerbations, because these particles are capable of reaching the distal regions of the lung, and have a greater surface area per unit mass for the generation of reactive oxygen species (6, 7).The rapid emergence of nanotechnology has led to the development of a multitude of engineered nanoparticles, namely, those defined a...

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