The &amp;#x201C;Classical&amp;#x201D; Ovalbumin Challenge Model of Asthma in Mice

Kumar, Rakesh K.; Herbert, Cristan; Foster, Paul S.

doi:10.2174/138945008784533561

Cited by 202 publications

(159 citation statements)

References 2 publications

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“…To determine whether asthma influences the abundance and distribution of TMEM16A protein in vivo, we sensitized C57BL/6 mice on days 0, 7, and 14 via i.p. injection of 50 μg OVA adsorbed in 2 mg alum gel in 200 μL PBS, and then challenged these mice with intranasal instillation of OVA (100 μg in 40 μL of saline) on days 21, 22, and 23 (14). Immunofluorescence with polyclonal antibodies against mouse TMEM16A (15) reveals a significant increase of TMEM16A protein in the airway epithelial cells of OVA-challenged mice (n = 5) compared with saline controls (Fig.…”

Section: Increased Expression Of Tmem16a In Epithelial Cells From Astmentioning

confidence: 97%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

291

314

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Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calciumactivated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.A sthma is a significant cause of morbidity and mortality worldwide, and the prevalence of this disease is increasing among all age, sex, and racial groups. Characteristic features of asthma include inflammation, subepithelial fibrosis, hyperplasia of mucus-producing cells, accumulation of mucus within airway lumens, hyperplasia of airway smooth muscle (ASM), and ASM hyperresponsiveness. Together, these symptoms impair lung function by limiting the flow of gases to and from the alveoli in the distal lung.The current standard of care for asthma involves inhaled corticosteroids for the management of inflammation combined with long-acting agonists of β2-adrenergic receptors. Despite this treatment, lung function is not improved in 30-45% of asthmatic patients, and exacerbations continue to be a major problem (reviewed in ref. 1). Asthma can be divided into at least two distinct molecular phenotypes defined by the degree of Th2 inflammation (2, 3). Cytokines, including IL-4 and IL-13, promote airway epithelial mucous cell metaplasia, subepithelial fibrosis, and hyperplasia of smooth muscle in Th2-high asthmatics, and these patients generally show improved lung function with inhaled corticosteroid therapy. A greater understanding of this heterogeneity and the molecular and physiological events that lead to airway remodeling might lead to improved diagnosis and treatment.Calcium-activated chloride channels (CaCCs) have been ascribed numerous cellular functions (reviewed in refs. 4 and 5), among these are epithelial fluid secretion and smooth muscle contraction, both of which contribute to the progression and severity of asthma. Moreover, calcium-activated chloride currents in the airway epithelium are enhanced by the Th2 cytokines IL-4 and IL-13, as well as IFN-γ (6). For these reasons, CaCC is an attractive potential therapeutic target for asthma (7). However, the study of CaCC was impeded by lack of information about the gene(s) encoding this channel. It was only relatively recently that TMEM16A (transmembrane p...

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Section: Increased Expression Of Tmem16a In Epithelial Cells From Astmentioning

confidence: 97%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

291

314

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“…Some of these are summarised in Table 1. The nature of the acute inflammatory model may be influenced by the choice of mouse strain, the allergen, and the sensitisation and challenge protocol (Zosky and Sly 2007;Kumar et al, 2008). The most commonly used strain of mouse for antigen challenge models is BALB/c as they develop a good T helper cell 2 (Th2)-biased immunological response (Boyce and Austen, 2005).…”

Section: Acute Allergen Challenge Modelsmentioning

confidence: 99%

Mouse models of allergic asthma: acute and chronic allergen challenge

Nials¹,

Uddin²

2008

Disease Models &Amp; Mechanisms

336

289

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Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiological and immunological processes are not fully understood. Animal models have been used to elucidate asthma pathophysiology, and to identify and evaluate novel therapeutic targets. Several recent review articles (Epstein, 2004; Lloyd, 2007; Boyce and Austen, 2005; Zosky and Sly, 2007) have discussed the potential value of these models. Allergen challenge models reproduce many features of clinical asthma and have been widely used by investigators; however, the majority involve acute allergen challenge procedures. It is recognised that asthma is a chronic inflammatory disease resulting from continued or intermittent allergen exposure, usually via inhalation, and there has been a recent focus on developing chronic allergen exposure models, predominantly in mice. Here, we review the acute and chronic exposure mouse models, and consider their potential role and impact in the field of asthma research.

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“…By using a factorial design, where allergic and nonallergic animals were exposed to the same air pollutants, it was possible to investigate if: (a) limonene, ozone, or their reaction products caused acute effects on respiration and inflammation in non-allergic mice; (b) limonene, ozone or their reaction products aggravated or attenuated an existing pulmonary allergic inflammation; and (c) the inflammatory and irritant responses to limonene, ozone or their reaction products differed between allergic and nonallergic mice. Standard mouse models of airway irritation based on head-out plethysmography (Alarie 1973;Nielsen et al 1999;Vijayaraghavan et al 1993) and airway allergy to the model allergen ovalbumin (OVA) (Kumar et al 2008) were used to test the hypotheses.…”

Section: Introductionmentioning

confidence: 99%

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice

Hansen

Nørgaard

Koponen

et al. 2016

Journal of Immunotoxicology

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Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Na€ ıve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone-limonene reaction mixture. Sensory and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast, it was found that limonene and the ozone-limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both na€ ıve and allergic mice. However, allergic but not na€ ıve mice were protected from pulmonary irritation induced by ozone. This study showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, antiinflammatory properties of the tested limonene-containing pollutants might attenuate airway allergy. ARTICLE HISTORY

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The “Classical” Ovalbumin Challenge Model of Asthma in Mice

Cited by 202 publications

References 2 publications

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Mouse models of allergic asthma: acute and chronic allergen challenge

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice

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