Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice

Ahmad, Tanveer; Mabalirajan, Ulaganathan; Hasija, Kanika; Ghosh, Balaram; Agrawal, Anurag

doi:10.1016/j.intimp.2010.10.008

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…In our previous study, we demonstrated that another PLA2 inhibitor, mepacrine, was able to reverse established airway remodeling [12]; mepacrine was administered for the last 2 weeks of the 4-week OVA challenge model. Various reports have demonstrated the reversal of airway remodeling with a 14-day treatment protocol [13,14].…”

Section: Methodsmentioning

confidence: 99%

Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β<sub>1</sub> in a Chronic Mouse Model of Allergic Asthma

Ram

Mabalirajan²,

Jaiswal³

et al. 2015

Int Arch Allergy Immunol

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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 Masson's 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.

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Section: Methodsmentioning

confidence: 99%

Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β<sub>1</sub> in a Chronic Mouse Model of Allergic Asthma

Ram

Mabalirajan²,

Jaiswal³

et al. 2015

Int Arch Allergy Immunol

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“…Total lung collagen content was measured by sircol assay (Biocolor Life Science Assays, Carrickfergus, UK) as described previously (18).…”

Section: Measurement Of Cx3cr1 and Tunel Apoptotic Assaymentioning

confidence: 99%

Hypoxia Response in Asthma

Ahmad

Kumar²,

Mabalirajan³

et al. 2012

Am J Respir Cell Mol Biol

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Oxygen-sensing prolyl-hydroxylase (PHD)-2 negatively regulates hypoxia-inducible factor (HIF)1-α and suppresses the hypoxic response. Hypoxia signaling is thought to be proinflammatory but also attenuates cellular injury and apoptosis. Although increased hypoxic response has been noted in asthma, its functional relevance is unknown. The objectives of this study were to dissect the mechanisms and role of the hypoxic response in asthma pathophysiology. Experimental studies were conducted in mice using acute and chronic allergic models of asthma. The hypoxic response in allergically inflamed lungs was modulated by using pharmacologic PHD inhibitors (ethyl-3-4-dihydroxybenzoic acid [DHB], 1-10 mg/kg) or siRNA-mediated genetic knockdowns. Increased hypoxia response led to exacerbation of the asthma phenotype, with HIF-1α knockdown being beneficial. Chronically inflamed lungs from mice treated with 10 mg/kg DHB showed diffuse up-regulation of the hypoxia response, severe airway remodeling, and inflammation. Fatal asphyxiation during methacholine challenge was noted. However, bronchial epithelium restricted up-regulation of the hypoxia response seen with low-dose DHB (1 mg/kg) reduced epithelial injury and attenuated the asthmatic phenotype. Up-regulation of the hypoxia response was associated with increased expression of CX3CR1, a lymphocyte survival factor, and increased inflammatory cell infiltrate. This study shows that an exaggerated hypoxia response may contribute to airway inflammation, remodeling, and the development of asthma. However, the hypoxia response may also be protective of epithelial apoptosis at lower levels, and the net effects of modulating the hypoxia response may vary based on the context.

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“…[55][56][57][58][59] Studies have identified elevated production of IgE and several inflammatory cytokines that lead to lung function abnormalities. 58,[60][61][62][63][64] Previous findings from our group and others have indicated that eosinophil recruitment into inflammatory tissue is a complex process regulated by Th2 cytokines (IL-5, IL-13, and IL-15) and eosinophilassociated chemokines in asthma pathogenesis. 12,13,65,66 Asthma patients tend to have both food and aeroallergen hypersensitivity.…”

Section: Discussionmentioning

confidence: 96%

“…The burden of immune‐related diseases, including asthma, is increasing globally, particularly in the Western world 53,54 Most asthma studies are focused largely on analyses of the cellular and molecular events induced by allergen exposure in sensitized animals and humans 55‐59 . Studies have identified elevated production of IgE and several inflammatory cytokines that lead to lung function abnormalities 58,60‐64 . Previous findings from our group and others have indicated that eosinophil recruitment into inflammatory tissue is a complex process regulated by Th2 cytokines (IL‐5, IL‐13, and IL‐15) and eosinophil‐associated chemokines in asthma pathogenesis 12,13,65,66 .…”

Section: Discussionmentioning

confidence: 99%

Role of IL‐18‐transformed CD274‐expressing eosinophils in promoting airway obstruction in experimental asthma

Mishra

Majid

Kandikattu

et al. 2021

Allergy

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Background IL‐5‐dependent residential and IL‐18‐transformed pathogenic eosinophils have been reported; however, the role of IL‐18‐transformed CD274‐expressing pathogenic eosinophils compared to IL‐5‐generated eosinophils in promoting airway obstruction in asthma has not yet been examined. Methods Eosinophils are detected by tissue anti‐MBP and anti‐EPX immunostaining, CD274 expression by flow cytometry, and airway resistance using the Buxco FinePointe RC system. Results We show that A. fumigatus‐challenged wild‐type mice, and different gene‐deficient mice including naïve CC10‐IL‐18‐transgenic mice, accumulate mostly peribronchial and perivascular CD274‐expressing eosinophils except naïve CD2‐IL‐5‐transgenic mice. Additionally, we show that CD2‐IL‐5 transgenic mice following rIL‐18 treatment accumulate high number of CD274‐expressing perivascular and peribronchial eosinophils with induced collagen, goblet cell hyperplasia and airway resistance compared to saline‐challenged CD2‐IL5 transgenic mice. Furthermore, we also show that even A. fumigatus‐challenged IL‐5 −/− mice and rIL‐18 given ΔdblGATA mice accumulate CD274‐expressing eosinophil‐associated asthma pathogenesis including airway obstruction. Most importantly, we provide evidence that neutralization of CD274 and IL‐18 in A. fumigatus‐challenged mice ameliorate experimental asthma. Taken together, the data presented are clinically significant in establishing that anti‐IL‐18 neutralization is a novel immunotherapy to restrict asthma pathogenesis. Conclusions We demonstrate that IL‐18 is critical for inducing asthma pathogenesis, and neutralization of CD274 is a potential immunotherapeutic strategy for asthma.

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Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice

Cited by 9 publications

References 29 publications

Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β<sub>1</sub> in a Chronic Mouse Model of Allergic Asthma

Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β<sub>1</sub> in a Chronic Mouse Model of Allergic Asthma

Hypoxia Response in Asthma

Role of IL‐18‐transformed CD274‐expressing eosinophils in promoting airway obstruction in experimental asthma

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