Feno differentiates epithelial gene expression clusters: Exploratory analysis from the MESOS randomized controlled trial

Diver, Sarah; Sridhar, Srinivas; Khalfaoui, Latifa; Russell, Richard J.; Emson, Claire; Griffiths, José-Marie; Reyes, Melissa de los; Yin, Desuo; Colice, Gene

doi:10.1016/j.jaci.2022.04.024

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…In addition, peripheral blood eosinophil counts and percentages, FeNO, serum IL‐13, and periostin levels were positively correlated with serum CST1 expression levels in patients with asthma. Consistent with our findings, Diver and co‐workers also found that CST1 mRNA expression was closely associated with T2 inflammation in an observational study 57 …”

Section: Discussionsupporting

confidence: 92%

“…Consistent with our findings, Diver and co-workers also found that CST1 mRNA expression was closely associated with T2 inflammation in an observational study. 57 The allergic asthmatic response to allergen exposure is associated with IgE-mediated mast cell activation, resulting in the accumulation of leukocytes such as eosinophils and Th2 lymphocytes in the airway. 58 We found that serum CST1 protein levels were not F I G U R E 4 HDM-induced epithelial barrier function disruption was suppressed by rhCST1 protein.…”

Section: Discussionmentioning

confidence: 99%

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Epithelium‐derived cystatin SN inhibits house dust mite protease activity in allergic asthma

Yao

Yuan

et al. 2023

Allergy

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Background Allergen source‐derived proteases are a critical factor in the formation and development of asthma. The cysteine protease activity of house dust mite (HDM) disrupts the epithelial barrier function. The expression of cystatin SN (CST1) is elevated in asthma epithelium. CST1 inhibits the cysteine protease activity. We aimed to elucidate the role of epithelium‐derived CST1 in the development of asthma caused by HDM. Methods CST1 protein levels in sputum supernatants and serum of patients with asthma and healthy volunteers were measured by ELISA. The ability of CST1 protein to suppress HDM‐induced bronchial epithelial barrier function was examined in vitro. The effects of exogenous CST1 protein on abrogating HDM‐induced epithelial barrier function and inflammation were examined in mice in vivo. Results CST1 protein levels were higher in sputum supernatants (142.4 ± 8.95 vs 38.87 ± 6.85 ng/mL, P < 0.0001) and serum (1129 ± 73.82 vs 703.1 ± 57.02 pg/mL, P = 0.0035) in patients with asthma than in healthy subjects. The levels were significantly higher in patients with not well‐ and very poorly controlled asthma than those with well‐controlled asthma. Sputum and serum CST1 protein levels were negatively correlated with lung function in asthma. CST1 protein levels were significantly lower in the serum of HDM‐specific IgE (sIgE)‐positive asthmatics than in sIgE‐negative asthmatics. The HDM‐induced epithelial barrier function disruption was suppressed by recombinant human CST1 protein (rhCST1) in vitro and in vivo. Conclusion Our data indicated that human CST1 protein suppresses asthma symptoms by protecting the asthmatic bronchial epithelial barrier through inhibiting allergenic protease activity. CST1 protein may serve as a potential biomarker for asthma control.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Epithelium‐derived cystatin SN inhibits house dust mite protease activity in allergic asthma

Yao

Yuan

et al. 2023

Allergy

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“…Nitric oxide is produced primarily in the bronchial epithelium by inducible nitric oxide synthase. Increased expression of T2 cytokines such as IL-4 and IL-13 results in overexpression of inducible nitric oxide synthase and increased F ENO levels, which further promotes T2 inflammation [ 96 , 97 ]. Chronic inflammation and frequent exacerbations can lead to a reduction in lung function, typically assessed as a decrease in the forced expiratory volume in 1 s (FEV 1 ) [ 98 ].…”

Section: Immune Hyperreactivitymentioning

confidence: 99%

The airway epithelium: an orchestrator of inflammation, a key structural barrier and a therapeutic target in severe asthma

Russell,

Boulet,

Brightling

et al. 2024

Eur Respir J

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Asthma is a disease of heterogeneous pathology, typically characterized by excessive inflammatory and bronchoconstrictor responses to the environment. The clinical expression of the disease is a consequence of the interaction between environmental factors and host factors over time, including genetic susceptibility, immune dysregulation and airway remodelling. As a critical interface between the host and the environment, the airway epithelium plays an important role in maintaining homeostasis in the face of environmental challenges. Disruption of epithelial integrity is a key factor contributing to multiple processes underlying asthma pathology. In this review, we first discuss the unmet need in asthma management and provide an overview of the structure and function of the airway epithelium. We then focus on key pathophysiological changes that occur in the airway epithelium, including epithelial barrier disruption, immune hyperreactivity, remodelling, mucus hypersecretion and mucus plugging, highlighting how these processes manifest clinically and how they might be targeted by current and novel therapeutics.

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“…All of these measurements aim to detect the Type 2-high inflammatory endotype and are not perfectly correlated due to differences in background cytokine regulation. Therefore, respective or mixed positivity indicates another signal in the disease pathology or a slightly different inflammation phenotype, thus supporting the use of a different treatment strategy [ 152 ]. It is, therefore, a frequent issue that one patient may be eligible for more therapeutic approaches.…”

Section: What Questions Regarding Eosinophils In Asthma Remain To Be ...mentioning

confidence: 99%

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

Novosad

Krčmová

Souček

et al. 2023

IJMS

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The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term “eosinophils” was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. Eosinophils may also be responsible for various possible tissue pathologies in many eosinophil-associated diseases. Since the beginning of the 21st century, the understanding of the nature of this cell population has undergone a fundamental reassessment, and in 2010, J. J. Lee proposed the concept of “LIAR” (Local Immunity And/or Remodeling/Repair), underlining the extensive immunoregulatory functions of eosinophils in the context of health and disease. It soon became apparent that mature eosinophils (in line with previous morphological studies) are not structurally, functionally, or immunologically homogeneous cell populations. On the contrary, these cells form subtypes characterized by their further development, immunophenotype, sensitivity to growth factors, localization, role and fate in tissues, and contribution to the pathogenesis of various diseases, including asthma. The eosinophil subsets were recently characterized as resident (rEos) and inflammatory (iEos) eosinophils. During the last 20 years, the biological therapy of eosinophil diseases, including asthma, has been significantly revolutionized. Treatment management has been improved through the enhancement of treatment effectiveness and a decrease in the adverse events associated with the formerly ultimately used systemic corticosteroids. However, as we observed from real-life data, the global treatment efficacy is still far from optimal. A fundamental condition, “sine qua non”, for correct treatment management is a thorough evaluation of the inflammatory phenotype of the disease. We believe that a better understanding of eosinophils would lead to more precise diagnostics and classification of asthma subtypes, which could further improve treatment outcomes. The currently validated asthma biomarkers (eosinophil count, production of NO in exhaled breath, and IgE synthesis) are insufficient to unveil super-responders among all severe asthma patients and thus give only a blurred picture of the adepts for treatment. We propose an emerging approach consisting of a more precise characterization of pathogenic eosinophils in terms of the definition of their functional status or subset affiliation by flow cytometry. We believe that the effort to find new eosinophil-associated biomarkers and their rational use in treatment algorithms may ameliorate the response rate to biological therapy in patients with severe asthma.

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Feno differentiates epithelial gene expression clusters: Exploratory analysis from the MESOS randomized controlled trial

Cited by 9 publications

References 39 publications

Epithelium‐derived cystatin SN inhibits house dust mite protease activity in allergic asthma

Epithelium‐derived cystatin SN inhibits house dust mite protease activity in allergic asthma

The airway epithelium: an orchestrator of inflammation, a key structural barrier and a therapeutic target in severe asthma

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

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