Chronic HDM exposure shows time-of-day and sex-based differences in inflammatory response associated with lung circadian clock disruption

Srinivasan, Ashokkumar; Giri, Allan; Duraisamy, Santhosh Kumar; Alsup, Alexander; Castro, Mario; Sundar, Isaac Kirubakaran

doi:10.1016/j.isci.2023.107580

Cited by 5 publications

(2 citation statements)

References 62 publications

(70 reference statements)

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“…In the current experiment, we chose to evaluate the pharmacological effects of Bronchom in female mice, on the basis of a previously published comprehensive study, which solely characterized the development of HDM induced-chronic airway inflammation and airway remodeling in mice (8). Furthermore, previously reported studies have established that female mice are more prone for the development of chronic asthma, subsequent to challenge with HDM, largely due to Th2 cytokine release and humoral response, resulting in higher numbers of eosinophils and more responsiveness to methacholine, when compared to male animals (22,23). The test article, Bronchom demonstrated promising efficacy by reducing the development of HDM-induced functional, cytological, histopathological, biochemical and molecular alterations.…”

Section: Discussionmentioning

confidence: 99%

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines

Balkrishna,

Sinha,

Karumuri

et al. 2024

Front. Immunol.

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BackgroundAsthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy, leading to a poorly-controlled disease state, necessitating the development of novel therapies. Bronchom is a calcio-herbal formulation, which is purported to treat chronic asthma. The objective of the current study was to examine the in-vivo efficacy of Bronchom in mouse model of allergic asthma.MethodsUltra high performance liquid chromatography was utilized to analyze the phytocompounds in Bronchom. Further, the in-vivo efficacy of Bronchom was evaluated in House dust mite (HDM)-induced allergic asthma in mice. Mice were challenged with aerosolized methacholine to assess airway hyperresponsiveness. Subsequently, inflammatory cell influx was evaluated in bronchoalveolar lavage fluid (BALF) followed by lung histology, wherein airway remodeling features were studied. Simultaneously, the levels of Th2 cytokines and chemokines in the BALF was also evaluated. Additionally, the mRNA expression of pro-inflammatory and Th2 cytokines was also assessed in the lung along with the oxidative stress markers.ResultsPhytocompounds present in Bronchom included, gallic acid, protocatechuic acid, methyl gallate, rosmarinic acid, glycyrrhizin, eugenol, 6-gingerol and piperine. Bronchom effectively suppressed HDM-induced airway hyperresponsiveness along with the influx of leukocytes in the BALF. Additionally, Bronchom reduced the infiltration of inflammatory cells in the lung and it also ameliorated goblet cell metaplasia, sub-epithelial fibrosis and increase in α-smooth muscle actin. Bronchom decreased Th2 cytokines (IL-4 and IL-5) and chemokines (Eotaxin and IP-10) in the BALF. Likewise, it could also suppress the mRNA expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6 and IL-33), and IL-13. Moreover, Bronchom restored the HDM-induced diminution of endogenous anti-oxidants (GSH and SOD) and the increase in pro-oxidants (GSSG and MDA). Furthermore, Bronchom could also decrease the nitrosative stress by lowering the observed increase in nitrite levels.ConclusionTaken together, the results of the present study data convincingly demonstrate that Bronchom exhibits pharmacological effects in an animal model of allergic asthma. Bronchom mitigated airway hyperresponsiveness, inflammation and airway remodeling evoked by a clinically relevant allergen and accordingly it possesses therapeutic potential for the treatment of asthma.

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Section: Discussionmentioning

confidence: 99%

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines

Balkrishna,

Sinha,

Karumuri

et al. 2024

Front. Immunol.

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“…The above‐mentioned findings corroborate with lung function parameters that showed significantly reduced lung function at ZT0 versus ZT12 BLM group for time‐of‐day response. Existing studies from the circadian clock in lung injury models conduct exposures and functional measurements at the same time to determine time‐of‐day response (e.g., ZT0 vs. ZT12) (Durrington et al, 2020 ; Hwang et al, 2014 ; Srinivasan et al, 2023 ; Wang et al, 2023 ). Hence, we followed a similar experimental design for the BLM‐induced lung injury model to measure lung function changes post‐BLM challenge at ZT0 or ZT12.…”

Section: Discussionmentioning

confidence: 99%

Lung mechanics showing sex‐based differences and circadian time‐of‐day response to bleomycin‐induced lung injury in mice

Prasad,

Duraisamy,

Sundar

2023

Physiological Reports

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Idiopathic pulmonary fibrosis (IPF) is a progressive disease that impairs lung mechanical properties due to dysregulated extracellular matrix remodeling. Lung function assessment is an important physiological endpoint in the mouse model of pulmonary fibrosis (PF) that has gained a broader scientific acceptance in the field. IPF pathophysiology shows sex‐based differences, disproportionately affecting more men compared to women. Prior reports suggest that the circadian clock is perturbed during the pathogenesis of PF. We have comprehensively assessed the sex‐based differences and time‐of‐day response (at Zeitgeber time: ZT0/6:00 a.m. or ZT12/6 p.m.) in lung mechanics among sham (control) versus bleomycin (BLM)‐challenged female and male (C57BL/6: WT) mice using Flexi‐vent. BLM challenge altered lung function significantly in males in both total lung (reduced dynamic compliance, and increased resistance and elastance) as well as lung tissue‐specific parameters (increased tissue elastance and tissue damping) but less pronounced in females. BLM‐challenged mice showed a time‐of‐day response in lung function at ZT0 versus ZT12, which was pronounced in the ZT0 BLM group. Overall, these findings provide a comprehensive analysis of altered lung function in female and male mice and the time‐of‐day difference in lung function parameters following BLM‐induced lung fibrosis.

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Melatonin regulates circadian clock proteins expression in allergic airway inflammation

Guo,

Jiang,

Chen

et al. 2024

Heliyon

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Chronic HDM exposure shows time-of-day and sex-based differences in inflammatory response associated with lung circadian clock disruption

Cited by 5 publications

References 62 publications

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines

Lung mechanics showing sex‐based differences and circadian time‐of‐day response to bleomycin‐induced lung injury in mice

Melatonin regulates circadian clock proteins expression in allergic airway inflammation

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