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Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma
허규영,David H. Broide 대한천식알레르기학회 2019 Allergy, Asthma & Immunology Research Vol.11 No.5
Asthma is a common disorder of the airways characterized by airway inflammation and by decline in lung function and airway remodeling in a subset of asthmatics. Airway remodeling is characterized by structural changes which include airway smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis due to thickening of the reticular basement membrane, mucus metaplasia of the epithelium, and angiogenesis. Epidemiologic studies suggest that both genetic and environmental factors may contribute to decline in lung function and airway remodeling in a subset of asthmatics. Environmental factors include respiratory viral infection-triggered asthma exacerbations, and tobacco smoke. There is also evidence that several asthma candidate genes may contribute to decline in lung function, including ADAM33, PLAUR, VEGF, IL13, CHI3L1, TSLP, GSDMB, TGFB1, POSTN, ESR1 and ARG2. In addition, mediators or cytokines, including cysteinyl leukotrienes, matrix metallopeptidase-9, interleukin-33 and eosinophil expression of transforming growth factor-β, may contribute to airway remodeling in asthma. Although increased airway smooth muscle is associated with reduced lung function (i.e. forced expiratory volume in 1 second) in asthma, there have been few long-term studies to determine how individual pathologic features of airway remodeling contribute to decline in lung function in asthma. Clinical studies with inhibitors of individual gene products, cytokines or mediators are needed in asthmatic patients to identify their individual role in decline in lung function and/or airway remodeling.
Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma
Lee, Jihyung,Kim, Tae Hoon,Murray, Fiona,Li, Xiangli,Choi, Sara S.,Broide, David H.,Corr, Maripat,Lee, Jongdae,Webster, Nicholas J. G.,Insel, Paul A.,Raz, Eyal National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.5
<P><B>Significance</B></P><P>Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsiveness and remodeling. However, the mechanisms by which DC promote Th2 differentiation remain unclear. Herein we demonstrate that low cAMP levels in DC induce Th2-biased responses in vitro and in vivo. Furthermore, mice with conditional deletion of <I>Gnas</I> in DC (<I>Gnas</I><SUP>ΔCD11c</SUP> mice) develop spontaneous bronchial asthma that shares multiple similarities with human asthma. In contrast, increasing cAMP levels inhibit these responses. Thus, regulators of cAMP levels in DC such as G-protein-coupled receptors are non-pattern recognition receptors that play a significant role in CD4 T cell differentiation.</P><P>The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of <I>Gnas</I>, the gene that encodes Gαs in mouse CD11c<SUP>+</SUP> cells (<I>Gnas</I><SUP>ΔCD11c</SUP> mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by <I>Gnas</I><SUP>ΔCD11c</SUP> DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.</P>
Achalasia During Pregnancy: Proposed Management Algorithm Based on a Thorough Literature Review
( Sergei Vosko ),( Daniel L Cohen ),( Ortal Neeman ),( Shai Matalon ),( Efrat Broide ),( Haim Shirin ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2021 Journal of Neurogastroenterology and Motility (JNM Vol.27 No.1
Fewer than 40 cases of achalasia occurring in pregnant woman have been reported in the literature. Given the rarity of achalasia during pregnancy, and the numerous treatment options that are available for achalasia in general, no guidelines exist for the management of achalasia during pregnancy. Diagnosis of new cases may be difficult as symptoms and physiological changes that occur during pregnancy may obscure the clinical presentation of achalasia. The management of achalasia in pregnancy is also challenging. Treatment decisions should be individualized for each case, considering both the welfare of the mother and the fetus. Since pregnant women suffering from achalasia represent a diagnostic and therapeutic challenge with complex maternal-fetal aspects to consider, we have reviewed the available literature on the subject and summarized current diagnostic and therapeutic options. Additionally, we present a management algorithm as a means to guide treatment of future cases. We recommend that a conservative approach should be adopted with bridging therapies performed until after delivery when definitive treatment of achalasia can be more safely performed. (J Neurogastroenterol Motil 2021;27:8-18)