Tag: Airway

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Decreased Epithelial and Plasma miR-181b-5p Expression Associates with Airway Eosinophilic Inflammation in Asthma.

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Decreased Epithelial and Plasma miR-181b-5p Expression Associates with Airway Eosinophilic Inflammation in Asthma.

Clin Exp Allergy. 2016 May 18;

Authors: Huo X, Zhang K, Yi L, Mo Y, Liang Y, Zhao J, Zhang Z, Xu Y, Zhen G

Abstract
BACKGROUND: Airway eosinophilic inflammation is a pivotal feature of asthma. Epithelial cells play critical roles in airway eosinophilia. We hypothesized that epithelial microRNAs (miRNAs) are involved in airway eosinophilia.
OBJECTIVE: This study investigated the associations between epithelial and plasma miR-181b-5p and airway eosinophilic inflammation, and the possible mechanism by which miR-181b-5p participates in eosinophilic inflammation.
METHODS: Epithelial miRNAs expression was profiled by miRNA array in 8 subjects with asthma and 4 healthy controls. Epithelial miR-181b-5p expression was confirmed by quantitative PCR in the subjects for array experiment and another cohort including 21 subjects with asthma and 10 controls. Plasma miR-181b-5p was determined by quantitative PCR in 72 subjects with asthma and 35 controls. Correlation assays between epithelial or plasma miR-181b-5p expression and airway eosinophilia were performed. The target of miR-181b-5p, SPP1, was predicted by online algorithms and verified in BEAS-2B cells. The role of miR-181b-5p in epithelial proinflammatory cytokine expression was examined in an in vitro system.
RESULTS: Epithelial miR-181b-5p expression was decreased in subjects with asthma. Epithelial miR-181b-5p levels were inversely correlated with sputum and bronchial submucosal eosinophilia. Plasma miR-181b-5p was decreased and correlated with epithelial miR-181b-5p in subjects with asthma. There was a strong inverse correlation between plasma miR-181b-5p and airway eosinophilia in subjects with asthma. Plasma miR-181b-5p was increased after inhaled corticosteroids treatment. We verified that SPP1 is a target of miR-181b-5p. In human bronchial epithelial cells, miR-181b-5p regulated IL-13-induced IL-1? and CCL11 expression by targeting SPP1. Dexamethasone restored IL-13-induced miR-181b-5p downregulation and suppressed IL-13-induced SPP1, IL-1? and CCL11 expression.
CONCLUSIONS AND CLINICAL RELEVANCE: Epithelial and plasma miR-181b-5p are potential biomarkers for airway eosinophilia in asthma. MiR-181b-5p may participate in eosinophilic airway inflammation by regulating proinflammatory cytokines expression via targeting SPP1. This article is protected by copyright. All rights reserved.

PMID: 27192552 [PubMed – as supplied by publisher]

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HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse.

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HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse.

J Immunol. 2016 Jan 29;

Authors: Wang Q, Li H, Yao Y, Lu G, Wang Y, Xia D, Zhou J

Abstract
The airway smooth muscle (ASM) cells’ proliferation, migration, and their progenitor’s migration are currently regarded as causative factors for ASM remodeling in asthma. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor, could promote ASM cell proliferation through MAPK pathways. In this study, we obtained primary ASM cells and their progenitors from C57BL/6 mice and went on to explore the role of HB-EGF in these cells migration and the underlying mechanisms. We found that recombinant HB-EGF (rHB-EGF) intratracheal instillation accelerated ASM layer thickening in an OVA-induced asthmatic mouse. Modified Boyden chamber assay revealed that rHB-EGF facilitate ASM cell migration in a dose-dependent manner and ASM cells from asthmatic mice had a greater migration ability than that from normal counterparts. rHB-EGF could stimulate the phosphorylation of ERK1/2 and p38 in ASM cells but further migration assay showed that only epidermal growth factor receptor inhibitor (AG1478) or p38 inhibitor (SB203580), but not ERK1/2 inhibitor (PD98059), could inhibit rHB-EGF-mediated ASM cells migration. Actin cytoskeleton experiments exhibited that rHB-EGF could cause actin stress fibers disassembly and focal adhesions formation of ASM cells through the activation of p38. Finally, airway instillation of rHB-EGF promoted the recruitment of bone marrow-derived smooth muscle progenitor cells, which were transferred via caudal vein, migrating into the airway from the circulation. These observations demonstrated that ASM remodeling in asthma might have resulted from HB-EGF-mediated ASM cells and their progenitor cells migration, via p38 MAPK-dependent actin cytoskeleton remodeling.

PMID: 26826248 [PubMed – as supplied by publisher]

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MiR-23b controls TGF-?1 induced airway smooth muscle cell proliferation via TGF?R2/p-Smad3 signals.

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MiR-23b controls TGF-?1 induced airway smooth muscle cell proliferation via TGF?R2/p-Smad3 signals.

Mol Immunol. 2015 Dec 31;70:84-93

Authors: Chen M, Huang L, Zhang W, Shi J, Lin X, Lv Z, Zhang W, Liang R, Jiang S

Abstract
BACKGROUND: Abnormal proliferation of ASM (airway smooth muscle) directly contributes to the airway remodeling during development of lung diseases such as asthma. Here we report that a specific microRNA (miR-23b) controls ASMCs proliferation through directly inhibiting TGF?R2/p-Smad3 pathway.
METHODS: The expression of miR-23b in ASMCs was detected by quantitative real-time polymerase chain reaction (RT-PCR). The effects of miR-23b on cell proliferation and apoptosis of ASMCs were assessed by transient transfection of miR-23b mimics and inhibitor. The target gene of miR-23b and the downstream pathway were further investigated.
RESULTS: Overexpression of miR-23b significantly inhibited TGF-?1-induced ASMCs proliferation and promoted apoptosis. RT-PCR and Western blotting analysis showed miR-23b negatively regulates the expression of TGF?R2 and p-Smad3 in ASMCs. Subsequent analyses demonstrated that TGF?R2 was a direct and functional target of miR-23b, which was validated by the dual luciferase reporter assay.
CONCLUSIONS: MiR-23b may function as an inhibitor of airway smooth muscle cells proliferation through inactivation of TGF?R2/p-Smad3 pathway.

PMID: 26748386 [PubMed – as supplied by publisher]

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Nuclear factor-?B mediates the phenotype switching of airway smooth muscle cells in a murine asthma model.

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Nuclear factor-?B mediates the phenotype switching of airway smooth muscle cells in a murine asthma model.

Int J Clin Exp Pathol. 2015;8(10):12115-28

Authors: Qiu C, Zhang J, Su M, Fan X

Abstract
Airway smooth muscle cells (ASMCs) phenotype modulation, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to airway proliferative diseases such as allergic asthma. Nuclear Factor-?B (NF-?B) has been reported as a key regulator for the occurrence and development of asthma. However, little is known regarding its role in ASM cell phenotypic modulation. To elucidate the role of NF-?B in regulating ASM cells phenotypic modulation, we investigated the effects of NF-?B on ASM cells contractile marker protein expression, and its impact on proliferation and apoptosis. We found that chronic asthma increased the activation of NF-?B in the primary murine ASM cells with a concomitant marked decrease in the expression of contractile phenotypic marker protein including smooth muscle alpha-actin (?-SMA). Additionally, we used the normal ASM cells under different processing to build the phenotype switching when we found the activation of NF-?B. Meanwhile, the expression of ?-SMA in asthma was significantly increased by the NF-?B blocker. NF-?B blocker also suppressed asthma mouse ASM cell proliferation and promoted apoptosis. These findings highlight a novel role for the NF-?B in murine ASM cell phenotypic modulation and provide a potential target for therapeutic intervention for asthma.

PMID: 26722396 [PubMed – in process]

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Apigenin inhibits TGF-?1-induced proliferation and migration of airway smooth muscle cells.

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Apigenin inhibits TGF-?1-induced proliferation and migration of airway smooth muscle cells.

Int J Clin Exp Pathol. 2015;8(10):12557-63

Authors: Li LH, Lu B, Wu HK, Zhang H, Yao FF

Abstract
It is well known that the proliferation and migration of ASM cells (ASMCs) plays an important role in the pathogenesis of airway remodeling in asthma. Previous studies reported that apigenin can inhibit airway remodeling in a mouse asthma model. However, its effects on the proliferation and migration of ASMCs in asthma remain unknown. Therefore, the aim of our present study was to investigate the effects of apigenin on ASMC proliferation and migration, and explore the possible molecular mechanism. We found that apigenin inhibited transforming growth factor-?1 (TGF-?1)-induced ASMC proliferation. The cell cycle was blocked at G1/S-interphase by apigenin. It also suppressed TGF-?1-induced ASMCs migration. Furthermore, apigenin inhibited TGF-?1-induced Smad 2 and Smad 3 phosphorylation in ASMCs. Taken together, these results suggested that apigenin inhibited the proliferation and migration of TGF-?1-stimulated ASMCs by inhibiting Smad signaling pathway. These data might provide useful information for treating asthma and show that apigenin has potential for attenuating airway remodeling.

PMID: 26722444 [PubMed – in process]

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Role of Local Eosinophilopoietic Processes in the Development of Airway Eosinophilia in Prednisone-dependent Severe Asthma.

Role of Local Eosinophilopoietic Processes in the Development of Airway Eosinophilia in Prednisone-dependent Severe Asthma.

Clin Exp Allergy. 2015 Dec 18;

Authors: Sehmi R, Smith SG, Kjarsgaard M, Radford K, Boulet LP, Lemiere C, Prazma CM, Ortega H, Martin JG, Nair P

Abstract
RATIONALE: In severe asthmatics with persistent airway eosinophilia, blockade of the eosinophilopoietin, interleukin-5 has significant steroid sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to airway eosinophilia in these patients is not known. We hypothesize that local eosinophilopoietic processes may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics.
METHODS: In a cross-sectional study, the number and growth potential of eosinophil-lineage committed progenitors (EoP) were assayed in 21 severe eosinophilic asthmatics, 19 mild asthmatics, 8 COPD patients and 8 normal subjects. The effect of anti-IL-5 treatment on mature eosinophils and EoP numbers was made in severe eosinophilic asthmatics who participated in a randomized clinical trial of mepolizumab (sub-study of a larger GSK sponsored global phase III trial, MEA115575) where subjects received mepolizumab (100 mg, n=9) or placebo (n=8), as six monthly subcutaneous injections.
RESULTS: Mature eosinophil and EoP numbers were significantly greater in the sputum of severe asthmatics compared with all other subject groups. In colony forming assays, EoP from blood of severe asthmatics demonstrated a greater response to IL-5 than mild asthmatics. Treatment of severe asthmatics with mepolizumab significantly attenuated blood eosinophils and increased EoP. There was however no significant treatment effect on mature eosinophils, sputum EoP numbers or the prednisone maintenance dose.
CONCLUSIONS: Patients with severe eosinophilic asthma have an exaggerated eosinophilopoeitic process in their airways. Treatment with 100 mg sub-cutaneous mepolizumab significantly attenuated systemic differentiation of eosinophils, but did not suppress local airway eosinophil differentiation to mature cells. Targeting IL-5 driven eosinophil differentiation locally within the lung maybe of relevance for optimal control of airway eosinophilia and asthma. This article is protected by copyright. All rights reserved.

PMID: 26685004 [PubMed – as supplied by publisher]

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Cyclooxygenase 2: its regulation, role and impact in airway inflammation.

Cyclooxygenase 2: its regulation, role and impact in airway inflammation.

Clin Exp Allergy. 2015 Dec 18;

Authors: Rumzhum NN, Ammit AJ

Abstract
Cyclooxygenase 2 (COX-2: official gene symbol – PTGS2) has long been regarded as playing a pivotal role in the pathogenesis of airway inflammation in respiratory diseases including asthma. COX-2 can be rapidly and robustly expressed in response to a diverse range of pro-inflammatory cytokines and mediators. Thus, increased levels of COX-2 protein and prostanoid metabolites serve as key contributors to pathobiology in respiratory diseases typified by dysregulated inflammation. But COX-2 products may not be all bad: prostanoids can exert anti-inflammatory/bronchoprotective functions in airways in addition to their pro-inflammatory actions. Herein we outline COX-2 regulation and review the diverse stimuli known to induce COX-2 in the context of airway inflammation. We discuss some of the positive and negative effects that COX-2/prostanoids can exert in in vitro and in vivo models of airway inflammation, and suggest that inhibiting COX-2 expression to repress airway inflammation may be too blunt an approach; because although it might reduce the unwanted effects of COX-2 activation, it may also negate the positive effects. Evidence suggests that prostanoids produced via COX-2 upregulation show diverse actions (and herein we focus on prostaglandin E2 as a key example); these can be either beneficial or deleterious and their impact on respiratory disease can be dictated by local concentration and specific interaction with individual receptors. We propose that understanding the regulation of COX-2 expression and associated receptor-mediated functional outcomes may reveal number of critical steps amenable to pharmacological intervention. These may prove invaluable in our quest towards future development of novel anti-inflammatory pharmacotherapeutic strategies for the treatment of airway diseases. This article is protected by copyright. All rights reserved.

PMID: 26685098 [PubMed – as supplied by publisher]

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