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

Ram, Arjun; Mabalirajan, Ulaganathan; Singh, Shashi Kant; Singh, Vijay Pal; Ghosh, Balaram

doi:10.1016/j.intimp.2008.02.005

Cited by 19 publications

(16 citation statements)

References 30 publications

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“…TGase 2 is expressed in the asthmatic airway epithelium (Hallstrand et al, 2010), and induces airway inflammation and structural remodelling in asthma by acting on the PLA2-cysteinyl-LTs axis (Bowton et al, 1997;Henderson et al, 2007;Ram et al, 2008;Mehrotra and Henderson, 2009;Hallstrand et al, 2010). Our data also suggest that R2 peptide reduced PLA2 activity by suppressing TGase 2 expression via regulating NF-kB activation in BAL cells and lung epithelial cells of OVA-challenged mice.…”

Section: Discussionsupporting

confidence: 54%

Anti‐inflammatory effects of the R2 peptide, an inhibitor of transglutaminase 2, in a mouse model of allergic asthma, induced by ovalbumin

Kim

Park

Hong

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSETransglutaminase 2 (TGase 2) expression is increased in inflammatory diseases, and TGase 2 inhibitors block these increases. We examined whether the R2 peptide inhibited the expression of TGase 2 in a mouse model of inflammatory allergic asthma. EXPERIMENTAL APPROACHC57BL/6 mice were sensitized and challenged by ovalbumin (OVA) to induce asthma. OVA-specific serum IgE and leukotrienes (LTs) levels were measured by enzyme-linked immunosorbent assay. Recruitment of inflammatory cells into bronchoalveolar lavage (BAL) fluid or lung tissues and goblet cell hyperplasia were assessed histologically. Airway hyperresponsiveness was determined in a barometric plethysmographic chamber. Expression of TGase 2, eosinophil major basic protein (EMBP), the adhesion molecule vascular cell adhesion molecule-1, Muc5ac and phospholipase A2 (PLA2) protein were determined by Western blot. Expression of mRNAs of Muc5ac, cytokines, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were measured by reverse transcriptase-polymerase chain reaction and nuclear factor-kB (NF-kB) by electrophoretic mobility shift assay. KEY RESULTSR2 peptide reduced OVA-specific IgE levels; the number of total inflammatory cells, macrophages, neutrophils, lymphocytes and eosinophils in BAL fluid and the number of goblet cells. Airway hyperresponsiveness, TGase 2 and EMBP levels, mRNA levels of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-13, RANTES, tumour necrosis factor-a, and MMP2/9, Muc5ac, NF-kB activity, PLA2 activity and expressions, and LT levels in BAL cells and lung tissues were all reduced by R2 peptide. R2 peptide also restored expression of TIMP1/2. CONCLUSION AND IMPLICATIONSR2 peptide reduced allergic responses by regulating NF-kB/TGase 2 activity in a mouse model of allergic asthma. This peptide may be useful in the treatment of allergic asthma. AbbreviationsBAL, bronchoalveolar lavage; ELISA, enzyme-linked immunosorbent assay; EMBP, eosinophil major basic protein; EMSA, electrophoretic mobility shift assay; MMP, matrix metalloproteinase; NF-kB, nuclear factor-kappa B; OVA, ovalbumin; PAS, periodic acid-Schiff; PBS, phosphate buffered saline; PLA2, phospholipase A2; RT-PCR, reverse transcriptase-polymerase chain reaction; TGase 2, transglutaminase 2; TIMP, tissue inhibitor of matrix metalloproteinase BJP British Journal of Pharmacology

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Section: Discussionsupporting

confidence: 54%

Anti‐inflammatory effects of the R2 peptide, an inhibitor of transglutaminase 2, in a mouse model of allergic asthma, induced by ovalbumin

Kim

Park

Hong

et al. 2010

British J Pharmacology

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“…The cytokines IL-4 and IL-5 were measured in BAL fluid supernatant and OVA-specific IgE levels in sera were measured by enzyme-linked immunosorbent assay (ELISA), as described previously [14, 19]. Corticosterone in the BAL fluid was assessed using an ELISA kit obtained from Neogen (USA).…”

Section: Methodsmentioning

confidence: 99%

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

Ram

Singh

et al. 2008

Int Arch Allergy Immunol

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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.

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“…On day 33, each mouse was sacrificed, bronchoalveolar lavage was performed, and bronchoalveolar lavage fluids (BALF) were processed to separate cell pellets and supernatants as described earlier (20,21). Total cell and differential counts were performed with resultant cell pellets to determine the absolute number of cells (8).…”

Section: Bronchoalveolar Lavage and Sera Separationmentioning

confidence: 99%

“…Total cell and differential counts were performed with resultant cell pellets to determine the absolute number of cells (8). Blood was withdrawn by cardiac puncture and serum was separated as described previously (20,21).…”

Section: Bronchoalveolar Lavage and Sera Separationmentioning

confidence: 99%

Esculetin Restores Mitochondrial Dysfunction and Reduces Allergic Asthma Features in Experimental Murine Model

Mabalirajan

Dinda²,

Sharma

et al. 2009

The Journal of Immunology

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We recently showed that IL-4-dependent oxidative stress and mitochondrial dysfunction are associated with allergic asthma. IL-4 also induces a prooxidant enzyme, 15-lipoxygenase, which predominantly expresses in asthmatic bronchial epithelium and degrades mitochondria. Esculetin (6,7-dihydroxy-2H-1-benzopyran-2-one), a plant-derived coumarin and immunomodulator, was found to have potent bronchodilating property in carbachol-induced bronchoconstriction and also reduces mitochondrial dysfunction in neurological diseases. In this study, we evaluated its potential in restoring mitochondrial dysfunction and structural changes and anti-asthma property in a mouse model of experimental asthma. In this study, we found that esculetin treatment reduced airway hyperresponsiveness, Th2 response, lung eotaxin, bronchoalveolar lavage fluid eosinophilia, airway inflammation, and OVA-specific IgE. It also reduced the expression and metabolites of 15-lipoxygenase and lipid peroxidation which is an essential prerequisite for mitochondrial dysfunction. Interestingly, esculetin treatment restored the activity of cytochrome c oxidase of electron transport chain in lung mitochondria and expression of the third subunit of cytochrome c oxidase of electron transport chain in bronchial epithelium. It reduced the cytochrome c level and caspase 9 activity in lung cytosol and restored mitochondrial structural changes and lung ATP levels. In addition, esculetin reduced subepithelial fibrosis and TGF-β1 levels in the lung. These results suggest that esculetin not only restores mitochondrial dysfunction and structural changes but also alleviates asthmatic features.

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

Cited by 19 publications

References 30 publications

Anti‐inflammatory effects of the R2 peptide, an inhibitor of transglutaminase 2, in a mouse model of allergic asthma, induced by ovalbumin

Anti‐inflammatory effects of the R2 peptide, an inhibitor of transglutaminase 2, in a mouse model of allergic asthma, induced by ovalbumin

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

Esculetin Restores Mitochondrial Dysfunction and Reduces Allergic Asthma Features in Experimental Murine Model

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