The barrier hypothesis and Oncostatin M: Restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease

Pothoven, Kathryn L.; Schleimer, Robert P.

doi:10.1080/21688370.2017.1341367

Cited by 55 publications

(47 citation statements)

References 164 publications

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“…40,41 In addition, the deposition of these highly stable crystals leads to a secondary neutrophilic inflammation and NETosis, which leads to further damage to the tissue or epithelium and may lead to resistance to therapeutic interventions with glucocorticoids. [40][41][42][43] TREATMENT APPROACHES AND UNMET NEEDS Type 2 immune reactions in CRSwNP have been associated with asthma comorbidity, severity, and recurrence of nasal polyps after systemic GCS or surgical treatment. 6 Frequent oral GCS boosts per year and repeated surgeries are therefore a clear hint for type 2 CRSwNP.…”

Section: Type 2 Inflammation In Crswnpmentioning

confidence: 99%

Biologics for chronic rhinosinusitis with nasal polyps

Bachert

Zhang

Cavaliere

et al. 2020

Journal of Allergy and Clinical Immunology

124

101

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With the increasing recognition of the role of type 2 immune responses in chronic rhinosinusitis, its severity, recurrence, and comorbidities, several biologics targeting IL-4, IL-5, and IL-13 as well as IgE have been administered in small proof-of-concept studies. Recently, the first phase 3 trials have been reported with dupilumab, an IL-4 receptor antagonist, demonstrating a significant and clinically relevant reduction of the disease burden from polyp size and sinus involvement to symptoms and smell; these changes consecutively led to an important increase in quality of life. Finally, the biologic versus placebo treatment reduced the need for systemic glucocorticosteroids and sinus surgery significantly and clinically meaningfully. Dupilumab today is registered for the treatment of chronic rhinosinusitis with nasal polyps in Europe and the United States. Within a year, 2 further phase 3 trials with omalizumab and mepolizumab will be reported. With this development, without any doubt, a new era for the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps has begun. Questions on the indication of the biologics, the selection of patients, and finally criteria for monitoring the efficacy in individual patients need to be urgently answered, and care pathways need to be established integrating the current standard of care including surgery.

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Section: Type 2 Inflammation In Crswnpmentioning

confidence: 99%

Biologics for chronic rhinosinusitis with nasal polyps

Bachert

Zhang

Cavaliere

et al. 2020

Journal of Allergy and Clinical Immunology

124

101

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“…Loss of epithelial barrier function reflects numerous inflammatory processes, including, most importantly, the metaplastic transformation of epithelial cells into goblet cells, a process mediated especially by IL-13, as occurs perhaps most importantly in the metaplastic transformation of epithelial cells into goblet cells as well as the more recently recognized process of epithelial mesenchymal transition. These processes mediated especially by IL-13 in the former and driven by numerous mediators but especially ascribed to amphiregulin and oncostatin M. 6…”

mentioning

confidence: 99%

Chronic rhinosinusitis: Endotypes, biomarkers, and treatment response

Gurrola

Borish

2017

Journal of Allergy and Clinical Immunology

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It is increasingly recognized that chronic rhinosinusitis (CRS) comprises a spectrum of different diseases with distinct clinical presentations and pathogenic mechanisms. Defining the distinct phenotypes and endotypes of CRS affects prognosis and, most importantly, is necessary as the basis for making therapeutic decisions. The need for individualized definitions of pathogenic mechanisms before initiating therapy extends to virtually all therapeutic considerations. This is clearly crucial with antibiotics, where, barring an influence from their off-target anti-inflammatory pharmacologic effects, an understanding of the role of the individual biome predicts likelihood of therapeutic benefit. However, this need for identifying individual phenotypes and endotypes also extends to the agent that is currently considered the mainstay of treatment of CRS, specifically glucocorticoids. As with asthma, it is recognized that a large minority of patients with CRS have a steroid-resistant phenotype, identification of which will preclude use of these agents with their potential side effects. Identification of endotypes is also becoming increasingly imperative because targeted biotherapeutic agents, such as anti-IgE and anti-cytokine antibodies, are becoming available. These agents are likely to benefit patients in whom the targeted mediator is not only expressed but demonstrably driving a central mechanism in that patient. In summary, the treatment of CRS is at an exciting crossroad. On the positive side, numerous therapeutics are in development that seem likely to have a positive effect in our patients with this condition. The challenge is that these therapies will require targeted individualized treatments based on identifying subjects with the relevant endotype.

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“…In bronchi, gland volume may be up to 50-fold larger than the volume of surface goblet cells (5,6,(133)(134)(135). Gland acini are likely significant contributors to the airway cytokine milieu, particularly when barrier dysfunction occurs during chronic inflammation in CRS, COPD, asthma, or CF (136)(137)(138) and/or when gland hypertrophy and hyperplasia occur during COPD and asthma (25,27,28,30). Elevations of NPY may alter submucosal gland function by both reducing cAMP-driven CFTR-mediated secretion as well as enhancing production of cytokines like GM-CSF and IL-1b that are important in allergic inflammation (139)(140)(141)(142), airway neutrophil or eosinophil infiltration (143,144), and Th2 polarization (145)(146)(147).…”

Section: Discussionmentioning

confidence: 99%

Inverse regulation of secretion and inflammation in human airway gland serous cells by neuropeptides upregulated in allergy and asthma

McMahon

Kohanski

Tong

et al. 2019

Preprint

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Airway submucosal gland serous cells are sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and are important for fluid secretion in conducting airways from the nose down to small bronchi. We tested if serous cells from human nasal turbinate glands secrete bicarbonate (HCO3 -), important for mucus polymerization, during stimulation with the cAMP-elevating agonist vasoactive intestinal peptide (VIP) and if this requires CFTR. Isoalted serous cells stimulated with VIP exhibited a ~20% cAMP-dependent decrease in cell volume and a ~0.15 unit decrease in intracellular pH (pHi), reflecting activation of Cland HCO3secretion, respectively.Pharmacology, ion substitution, and studies using cells from CF patients suggest serous cell HCO3secretion is mediated by conductive efflux directly through CFTR. Interestingly, we found that neuropeptide Y (NPY) reduced VIP-evoked secretion by blunting cAMP increases and reducing CFTR activation through Gi-coupled NPY1R. Culture of primary gland serous cells in a model that maintained a serous phenotype confirmed the activating and inhibiting effects of VIP and NPY, respectively, on fluid and HCO3secretion. Moreover, VIP enhanced secretion of antimicrobial peptides and antimicrobial efficacy of gland secretions while NPY reduced antimicrobial secretions. In contrast, NPY enhanced the release of cytokines during inflammatory stimuli while VIP reduced cytokine release through a mechanism requiring CFTR conductance. As levels of VIP and NPY are up-regulated in disease like allergy, asthma, and chronic rhinosinusitis, the balance of these two peptides in the airway may control airway mucus rheology and inflammatory responses through gland serous cells.

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The barrier hypothesis and Oncostatin M: Restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease

Cited by 55 publications

References 164 publications

Biologics for chronic rhinosinusitis with nasal polyps

Biologics for chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis: Endotypes, biomarkers, and treatment response

Inverse regulation of secretion and inflammation in human airway gland serous cells by neuropeptides upregulated in allergy and asthma

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