Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases

Journal of Leukocyte Biology, Journal Year: 2020, Volume and Issue: 107(5), P. 749 - 762

Published: Feb. 28, 2020

Abstract This review focuses on recent developments related to asthma, chronic rhinosinusitis, atopic dermatitis (AD), eosinophilic esophagitis, and inflammatory bowel diseases (IBD), with a particular focus tight junctions (TJs) their role in the pathogenetic mechanisms of these diseases. Lung, skin, intestinal surfaces are lined by epithelial cells that interact environmental factors immune cells. Therefore, together cellular system, epithelium performs pivotal as first line physical barrier against external antigens. Paracellular space is almost exclusively sealed TJs maintained complex protein-protein interactions. Thus, TJ dysfunction increases paracellular permeability, resulting enhanced flux across TJs. Epithelial also causes cell activation contributes pathogenesis lung, inflammation. Characterization protein alteration one key for enhancing our understanding allergic well IBDs. Furthermore, TJ-based disturbance can promote behaviors, such those dendritic cells, Th2 Th17 innate lymphoid (ILCs), thereby offering new insights into targets. The purpose this illustrate how lead disruption homeostasis tissues subsequent highlights various dysfunctions different organ sites, which would help develop future drugs target IBD.

Language: Английский

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Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study

Journal of the American Academy of Dermatology, Journal Year: 2021, Volume and Issue: 85(4), P. 854 - 862

Published: June 10, 2021

Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD).To evaluate the efficacy and safety of delgocitinib ointment pediatric AD.Part 1 this study was 4-week double-blind period which Japanese aged 2 through 15 years were randomized 1:1 ratio to 0.25% or vehicle ointment. Part 52-week extension period. Eligible entered part receive ointment.At initiation study, approximately half had moderate AD. At end treatment 1, least-squares mean percent change from baseline modified Eczema Area Severity Index score, primary endpoint, significantly greater than (-39.3% vs +10.9%, P < .001). In 2, improvements AD also seen week 56. Most adverse events mild unrelated across periods.Only included. no control group included rescue therapy allowed.Delgocitinib effective well tolerated when applied up 56 weeks.

Language: Английский

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The leukotriene receptors as therapeutic targets of inflammatory diseases

International Immunology, Journal Year: 2019, Volume and Issue: 31(9), P. 607 - 615

Published: May 27, 2019

Abstract Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid. LTs include the di-hydroxy acid LT (LTB4) and cysteinyl (CysLTs; LTC4, LTD4 LTE4), all of which involved in both acute chronic inflammation. We other groups identified a high-affinity LTB4 receptor, BLT1; LTC4 receptors, CysLT1 CysLT2; LTE4 GPR99. Pharmacological studies have shown that BLT1 signaling stimulates degranulation, chemotaxis phagocytosis neutrophils, whereas CysLT2 induces airway inflammation by increasing vascular permeability contraction bronchial smooth muscle. Recently, we suggested LTB4–BLT1 axis LTs–CysLT1/2 diseases including asthma, atopic dermatitis, psoriasis, atherosclerosis, arthritis, obesity, cancer age-related macular degeneration using animal models for disease gene knockout mice. This review describes classical novel functions their receptors several discusses potential clinical applications antagonists inhibitors biosynthesis.

Language: Английский

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Anti-TSLP antibodies: Targeting a master regulator of type 2 immune responses

Allergology International, Journal Year: 2020, Volume and Issue: 69(2), P. 197 - 203

Published: Jan. 21, 2020

TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses bacteria. Biological functions of require heterodimer formation between the receptor (TSLPR) IL-7 receptor-α, which polarize dendritic cells induce type 2 inflammation directly expand and/or activate Th2 cells, group innate lymphoid basophils, other immune cells. thus considered a master regulator responses at barrier surfaces skin respiratory/gastrointestinal tract. Indeed, genetic, experimental, clinical evidence suggests that TSLP-TSLPR pathway associated with pathogenesis allergic diseases such as atopic dermatitis (AD) asthma. Tezepelumab (AMG-157/MEDI9929) human anti-TSLP antibody prevents interactions. A phase trial for moderate severe AD showed greater but not statistically significant percentage tezepelumab-treated patients improvements compared placebo group. uncontrolled, asthma decreases exacerbation rate improved pulmonary function control patients. Levels biomarkers inflammation, blood/sputum eosinophil counts fraction exhaled nitric oxide decreased, however, efficacy was observed irrespective baseline levels these biomarkers. blockade likely will exert effects on AD, asthma, diseases. The antibodies biologics needs be further examined.

Language: Английский

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Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence

Nutrients, Journal Year: 2021, Volume and Issue: 13(12), P. 4550 - 4550

Published: Dec. 18, 2021

The role of the microbiome in human aging is important: directly impacts through gastrointestinal system. However, microbial impact on skin has yet to be fully understood. For example, cellular senescence an intrinsic process that been recently associated with imbalance. With age, cells become senescent response stress wherein they undergo irreversible growth arrest while maintaining high metabolic activity. An accumulation linked various and chronic pathologies due overexpression senescence-associated secretory phenotype (SASP) comprised proinflammatory cytokines, chemokines, factors, proteases, lipids extracellular matrix components. In particular, dermatological disorders may promoted by as a common site accumulation. gut microbiota influences disruption gut-skin axis secretion metabolites. Metabolomics can used identify quantify metabolites involved senescence. Moreover, novel anti-senescent therapeutics are warranted given poor safety profiles current pharmaceutical drugs. Probiotics prebiotics effective alternatives, considering relationship between healthy aging. further research composition under status needed develop immunomodulatory therapies.

Language: Английский

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