Arjun Ram

Luteolin alleviates bronchoconstriction and airway hyperreactivity in ovalbumin sensitized mice

Abstract:Objective and Design: Asthma is an inflammatory disease of the airways and the current focus in managing asthma is the control of inflammation. In this study, we attempted to investigate the anti-asthmatic potential of a plant derived natural compound, luteolin.¶Material: We used a murine model of airway hyperreactivity, which mimicked some of the characteristic features of asthma. Male BALB/c mice (8-9 weeks) were used for this study.¶Treatment: Mice (n = 6) were sensitized by intraperitoneal (i.p.) injection of 10 mg of ovalbumin (OVA) on days 0, 7 and 14 followed by aerosol inhalation (5 % OVA) treatments daily beginning from day 19 to day 23. To study its preventive effect, luteolin (0.1, 1.0, and 10 mg/kg body weight; daily) was administered orally during the entire period (0 to 23 day) of sensitization. To study its curative effect, mice were first sensitized and then luteolin (1.0 mg/kg body weight daily) was given orally from day 26 to 32. The airway hyperreactivity, immunoglobulin E (IgE) in the sera, and cytokines (IFN-γ, IL-4 and IL-5) in the bronchoalveolar lavage fluid (BALF) were measured.¶Results: Both during sensitization and after sensitization, luteolin, at a dose of 0.1 mg/kg body weight, significantly modulated OVA-induced airway bronchoconstriction and bronchial hyperreactivity (p < 0.05). Luteolin also reduced OVA-specific IgE levels in the sera, increased interferon gamma (IFN-γ) levels and decreased the interleukin-4 (IL-4) and interleukin-5 (IL-5) levels in the BALF.¶Conclusion: Our study showed that luteolin treatment during and after sensitization significantly attenuated the asthmatic features in experimental mice. Therefore, luteolin could be used either as a lead molecule to identify an effective anti-asthma therapy or as a means to identify novel anti-asthma targets.

Medicinal plants useful for treating chronic obstructive pulmonary disease (COPD): Current status and future perspectives

Chronic obstructive pulmonary disease (COPD) is a major global health problem. The current therapies are inadequate and have numerous adverse effects. There is an acute need of potential alternative therapies. Medicinal plants are classical and most widespread form of medication for treating various human ailments throughout the world. For COPD also, various plants are practiced in many countries. We have surveyed the literatures for the medicinal plants which are used in obstructive lung diseases such as bronchitis and emphysema. These plants were segregated into two categories. Firstly, the plants which are used for obstructive lung diseases based on various traditional recommendations only. Secondly, the plants or their formulations which have been studied grossly in COPD patients and animal models for their scientific validation. Further, we have described some known cellular and molecular factors involved in COPD and their modulation by plant-derived compounds. Certain future perspectives have also been discussed.

Mepacrine alleviates airway hyperresponsiveness and airway inflammation in a mouse model of asthma

Asthma is a multifactorial respiratory disease. Though its incidence is increasing rapidly all over the world, the available therapeutic strategies are neither sufficient nor safe for long term use. Mepacrine, a known antimalarial drug, has been shown to possess antioxidant, anti-inflammatory, platelet anti-aggregant, and PLA2 inhibitory activities. However, its possible use in asthma has not been studied yet. The objective of this study was to investigate the anti-asthmatic property of mepacrine using a mouse model of asthma. To accomplish this, male BALB/c mice were sensitized and challenged with ovalbumin and treated with increasing concentrations of mepacrine. Airway hyperresponsiveness (AHR) to methacholine was assessed using unrestrained whole body plethysmography. Mepacrine (1 mg/kg) has shown marked attenuation of AHR. Cytokines such as IL-4, IL-5, IL-13 and IFN-gamma and OVA-specific IgE levels were measured in BAL (bronchoalveloar lavage) fluid and sera, respectively. Mepacrine effectively reduced the rise in IL-4, IL-5, IL-13, and OVA-specific IgE and restored IFN-gamma levels. Mepacrine also significantly prevented the increase of sPLA2 (secretory phospholipase A2) activity in BAL fluid supernatant and Cys-LT (cysteinyl leukotrienes) in lung tissue homogenates of asthmatic mice. In addition, mepacrine treatment reduced BAL fluid eosinophilia and signs of allergic airway inflammation such as perivascular and peribronchial distribution of inflammatory cells. These findings indicate that mepacrine reduces the asthmatic features in ovalbumin induced asthma by acting on PLA2-Cys-LT axis. Thus, it could be useful for the development of better asthma therapy.

Inhaled Carbenoxolone Prevents Allergic Airway Inflammation and Airway Hyperreactivity in a Mouse Model of Asthma

Background: Asthma is a chronic respiratory disease, which needs a safer medication preferably in inhalation form. In view of this, we have evaluated the effect of inhaled carbenoxolone (CBX), a herbal-derived compound, on asthma in a mouse model. Methods: Mice were sensitized and challenged with ovalbumin (OVA) to develop certain characteristic features of asthma such as airway hyperreactivity (AHR), airway eosinophilia, lung inflammation and mucus hypersecretion. To evaluate the effect of CBX on the above asthmatic features, CBX (2.5, 5 and 10 mg/ml, 3 ml) or vehicle (water) was given by inhalation. AHR was determined using whole-body plethysmography. Infiltration of eosinophils was estimated by microscopy. Lung inflammation and mucus hypersecretion were assessed using hematoxylin and eosin, and periodic acid-Schiff staining, respectively. Th-2 cytokines, IL-4 and IL-5 were measured in bronchoalveolar lavage (BAL) fluid and IgE in sera. To identify the possible mode of CBX action, we measured corticosterone levels in the BAL fluid and 5-lipoxygenase (5-LO) expression in the lungs. Results: CBX (5 mg/ml) inhalation markedly alleviated AHR (p = 0.0032) and reduced lung inflammation and mucus hypersecretion. Also, it prevented the increase in IL-4 (p = 0.0192), IL-5 (p = 0.0116) and eosinophils (p < 0.0005) in the BAL fluid, and OVA-specific IgE levels (p = 0.00061) in sera. 5-LO expression was also markedly reduced. However, corticosterone levels were not affected. Conclusions: Inhaled CBX alleviates the asthmatic features in mice and could be a potent nebulized therapy in clinical asthma.

Basis of Rise in Intracellular Sodium in Airway Hyperresponsiveness and Asthma

The aim of this study was to investigate the basis of disturbances in sodium transport in asthma and in airway hyperresponsiveness without symptoms of asthma (asymptomatic AHR). We measured the intracellular sodium (Nai); activity of Na+/K+-ATPase in unstimulated cells (resting activity) and in cell homogenate under optimal conditions (maximal activity); and sodium influx, in mixed leukocytes of 15 normal subjects, 12 subjects with asymptomatic AHR, and 26 asthmatics with or without active symptoms. Resting Na+/K+-ATPase activity was the same as sodium influx, consistent with homeostasis. Compared with normal subjects, those with asymptomatic AHR or asthma with controlled symptoms had a twofold increase in sodium influx and Nai. Symptomatic asthmatics also had a twofold increase in sodium influx but a fourfold elevation of Nai. Maximal Na+/K+-ATPase activity was reduced by half in symptomatic asthmatics compared with normal subjects. The reduction of maximal Na+/K+-ATPase activity was associated with a significant decrease in ATP turnover per Na+/K+-ATPase molecule but not number of Na+/K+-ATPase molecules per cell. In summary, airway hyperresponsiveness with or without asthma is associated with increased sodium influx and Na in leukocytes. Resting activity of Na+/K+-ATPase is also increased as a compensatory response to the increased sodium influx, but it is achieved at the expense of higher Nai. Symptomatic asthma is additionally associated with reduction in maximal activity of Na+/K+-ATPase, resulting in reduced capacity to handle the increase in sodium influx and consequent severe elevations in Nai.

Novel Approaches for Inhibition of Mucus Hypersecretion in Asthma

Many obstructive airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD) are characterized by mucous metaplasia of the airway epithelium and chronic mucus hypersecretion. Airway occlusion by mucus plugging has been reported in many cases of fatal asthma and conventional mucolytic therapies have been unable to significantly affect mucus-related airway obstruction. Recently, for the first time, direct evidence was presented for improvement of mucus related airway obstruction in a murine model of asthma, highlighting the potential usefulness of therapeutically targeting mucus hypersecretion. We review the emerging targets for inhibition of mucus hypersecretion and discuss some of the recent published scientific literature and patent applications in this field, to provide a framework for further drug discovery in mucus modulation.

Parabromophenacyl bromide inhibits subepithelial fibrosis by reducing TGF-β1 in a chronic mouse model of allergic asthma.

Background: Our previous study showed that parabromophenacyl bromide (PBPB) inhibits the features of allergic airway inflammation and airway hyperresponsiveness (AHR). However, its effect on airway remodeling, e.g. subepithelial fibrosis in a chronic allergic asthma model, was not investigated. We examined this issue in this study. Methods: PBPB was administered to mice with an induced chronic asthmatic condition. AHR was estimated at the end of the experiment, followed by euthanasia. Lung sections were stained with hematoxylin and eosin, periodic acid-Schiff and Massons trichrome to determine airway inflammation, goblet cell metaplasia and subepithelial fibrosis, respectively. Transforming growth factor-β1 (TGF-β1) was estimated in lung homogenates. To determine the effect of PBPB on smooth-muscle hyperplasia, immunohistochemistry against α-smooth-muscle actin was performed on the lung sections. Results: Chronic ovalbumin challenges in a mouse model of allergic asthma caused significant subepithelial fibrosis and elevated TGF-β1, along with significant AHR. PBPB attenuated subepithelial fibrosis with a reduction of lung TGF-β1, airway inflammation and AHR without affecting goblet cell metaplasia. It also attenuated smooth-muscle hyperplasia with a reduction in the expression of α-smooth-muscle actin in the lungs. Conclusion: Our findings indicate that PBPB attenuates some crucial features of airway remodeling such as subepithelial fibrosis and smooth-muscle hyperplasia. These data suggest that PBPB could therefore be a therapeutic drug for chronic asthma.

House dust mite allergen causes certain features of steroid resistant asthma in high fat fed obese mice

ABSTRACT Obesity is a high risk factor for diseases such as cardiovascular, metabolic syndrome and asthma. Obese‐asthma is another emerging phenotype in asthma which is typically refractive to steroid treatment due to its non‐classical features such as non‐eosinophilic cellular inflammation. The overall increased morbidity, mortality and economical burden in asthma is mainly due to steroid resistant asthma. In the present study, we used high fat diet induced obese mice which when sensitized with house dust mite (HDM) showed steroid resistant features. While the steroid, dexamethasone (DEX), treatment to high fat fed naïve mice could not reduce the airway hyperresponsiveness (AHR) induced by high fat, DEX treatment to high fat fed allergic mice could not reduce the HDM allergen induced airway remodeling features though it reduced airway inflammation. Further, these HDM induced high fat fed mice with or without DEX treatment had shown the increased activity and expression of arginase as well as the inducible nitric oxide synthase (iNOS) expression. However, DEX treatment had reduced the expressions of high iNOS and arginase I in control chow diet fed mice. Thus, we speculate that the steroid resistance seen in human obese asthmatics could be stemming from altered NO metabolism and its induced airway remodeling and with further investigations, it would encourage new treatments specific to obese‐asthma phenotype. HighlightsObese‐asthma is another emerging phenotype in asthma which is typically refractive to steroid treatment.The steroid, dexamethasone, treatment to high fat fed obese mice could not reduce the airway hyperresponsiveness (AHR).The steroid treatment to obese‐allergic mice could not reduce the house dust mite induced airway remodeling.The steroid treatment to obese‐allergic mice could not reduce arginase and iNOS expressions.The steroid resistance seen in human obese asthmatics could be stemming from altered NO metabolism.