Mast cell chymase regulates extracellular matrix remodeling-related events in primary human small airway epithelial cells

Zhao, Xinran; Sommerhoff, Christian P.; Paivandy, Aida; Pejler, Gunnar

doi:10.1016/j.jaci.2022.05.028

Cited by 11 publications

(10 citation statements)

References 45 publications

(53 reference statements)

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“…The study also provided an enumeration of the degranulating mast cells; however, these observations relied on the morphometric appearances of granules within the cells rather than specific biomarkers. We also reported that smoking decreased large and small airway subepithelial lamina propria total cellularity in mild to moderate COPD patients [2,4,7,19]. However, we did not previously enumerate the contribution of MCs in the small airway and in the alveolar areas of smoker and COPD patients.…”

Section: Introductionmentioning

confidence: 82%

“…We also previously demonstrated the increase in airway wall thickness, especially in the lamina propria and smooth muscles, along with the increase in collagen and fibronectin deposition in smokers and COPD patients [ 3 ]. MC secretions have been observed to regulate the extracellular matrix (ECM) in airway epithelial cells [ 19 , 20 ]. However, few studies have critically assessed MCs and their association with airway remodelling and ECM changes in the small airways of smokers and COPD patients.…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD

Eapen,

Lu,

Dey

et al. 2024

ERJ Open Res

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BackgroundCOPD patients suffer from dysregulated and suppressed immune functionality, determined by their loss of degranulating capacity. Here we provide crucial information on the presence of degranulated MC in COPD airways and demonstrate their relationship to lung physiology and airway remodelling.MethodsSmall airway (SA) lung resections from non-smoking controls (NC), smokers with normal lung function (NLFS), small airway disease (SAD), mild-moderate COPD current smokers (CS), and ex-smokers (ES) were dual immuno-stained with mast cell tryptase and degranulation marker LAMP-1. Total MC, degranulating MC and non-MC were enumerated in SA epithelium and sub-epithelium, respectively, and in alveolar septa.ResultsIn the SA wall, sub-epithelial areas, COPD-CS and -ES had significantly lower mast cells than NC (p<0.05), though considerably higher in SA epithelium (p<0.01). Degranulating non-mast cells were higher in SAD (p<0.05) than in COPD in SA sub-epithelium. In contrast, there were significant increases in total mast cells (degranulated and non-degranulated) and degranulated non-mast cells in the alveolar septum of COPD patients compared to NC (p<001). The lower numbers of mast cells in the sub-epithelium correlated with lower FEV1/FVC and FEF25-75%, higher smoking rates in COPD patients, and increased SA wall thickness and ECM. The increase in the alveolar in mast cells negatively correlated with FEF 25-75%.ConclusionsThis study is the first to assess the differential pattern of mast cells, degranulating mast and non-mast cell populations in the SA and alveoli of COPD patients. The spatial positioning of the mast cells within the airways showed variable correlations with lung function.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD

Eapen,

Lu,

Dey

et al. 2024

ERJ Open Res

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“…This observation holds particular relevance to its association with major comorbidities such as EDS/hEDS/HSD. Mast cells and eosinophils, widely distributed in connective tissues ( 164 ), play crucial roles in immune regulation and extracellular matrix homeostasis ( 165 , 166 ).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal cytokine and multi-modal health data of an extremely severe ME/CFS patient with HSD reveals insights into immunopathology, and disease severity

Jahanbani,

Sing,

Maynard

et al. 2024

Front. Immunol.

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IntroductionMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health,textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies.MethodsThis study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention.ResultsLongitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression.DiscussionOur study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice.

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“…For example, the mast cell tryptase has been shown to mainly be pro-inflammatory in mouse models of asthma, contributing to airway hyperresponsiveness although tryptase also has the ability to degrade pro-inflammatory cytokines [10,28,29]. Similarly, mast cell chymase may exhibit both pro-and anti-inflammatory effects in the context of airway inflammation, as it has been shown that chymase can promote fibrosis by degradation of fibronectin and collagen [30] but can also reduce AHR [12,13] and degrade various type 2 cytokines and chemokines [31,32]. In contrast to tryptase and chymase, there is limited information regarding the possible roles of CPA3 in asthma.…”

Section: Plos Onementioning

confidence: 99%

Disruption of the mast cell carboxypeptidase A3 gene does not attenuate airway inflammation and hyperresponsiveness in two mouse models of asthma

Waern,

Akula,

Allam

et al. 2024

PLoS ONE

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Mast cells are effector cells known to contribute to allergic airway disease. When activated, mast cells release a broad spectrum of inflammatory mediators, including the mast cell-specific protease carboxypeptidase A3 (CPA3). The expression of CPA3 in the airway epithelium and lumen of asthma patients has been associated with a Th2-driven airway inflammation. However, the role of CPA3 in asthma is unclear and therefore, the aim of this study was to investigate the impact of CPA3 for the development and severity of allergic airway inflammation using knockout mice with a deletion in the Cpa3 gene. We used the ovalbumin (OVA)- and house-dust mite (HDM) induced murine asthma models, and monitored development of allergic airway inflammation. In the OVA model, mice were sensitized with OVA intraperitoneally at seven time points and challenged intranasally (i.n.) with OVA three times. HDM-treated mice were challenged i.n. twice weekly for three weeks. Both asthma protocols resulted in elevated airway hyperresponsiveness, increased number of eosinophils in bronchoalveolar lavage fluid, increased peribronchial mast cell degranulation, goblet cell hyperplasia, thickening of airway smooth muscle layer, increased expression of IL-33 and increased production of allergen-specific IgE in allergen-exposed mice as compared to mocktreated mice. However, increased number of peribronchial mast cells was only seen in the HDM asthma model. The asthma-like responses in Cpa3-/- mice were similar as in wild type mice, regardless of the asthma protocol used. Our results demonstrated that the absence of a functional Cpa3 gene had no effect on several symptoms of asthma in two different mouse models. This suggest that CPA3 is dispensable for development of allergic airway inflammation in acute models of asthma in mice.

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Mast cell chymase regulates extracellular matrix remodeling-related events in primary human small airway epithelial cells

Cited by 11 publications

References 45 publications

Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD

Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD

Longitudinal cytokine and multi-modal health data of an extremely severe ME/CFS patient with HSD reveals insights into immunopathology, and disease severity

Disruption of the mast cell carboxypeptidase A3 gene does not attenuate airway inflammation and hyperresponsiveness in two mouse models of asthma

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