scholarly journals Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

2016 ◽  
Vol 311 (2) ◽  
pp. L421-L432 ◽  
Author(s):  
Sarah K. Sasse ◽  
Mohammed O. Altonsy ◽  
Vineela Kadiyala ◽  
Gaoyuan Cao ◽  
Reynold A. Panettieri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Airway Epithelial Cells ◽  
Therapeutic Effects ◽  
Target Tissue ◽  
Airway Epithelial ◽  
Fatal Asthma

Airway smooth muscle is a major target tissue for glucocorticoid (GC)-based asthma therapies, however, molecular mechanisms through which the GC receptor (GR) exerts therapeutic effects in this key airway cell type have not been fully elucidated. We previously identified the nuclear factor-κB (NF-κB) inhibitor, A20 (TNFAIP3), as a mediator of cytokine repression by glucocorticoids (GCs) in airway epithelial cells and defined cooperative regulation of anti-inflammatory genes by GR and NF-κB as a key mechanistic underpinning of airway epithelial GR function. Here, we expand on these findings to determine whether a similar mechanism is operational in human airway smooth muscle (HASM). Using HASM cells derived from normal and fatal asthma samples as an in vitro model, we demonstrate that GCs spare or augment TNF-mediated induction of A20 ( TNFAIP3), TNIP1, and NFKBIA, all implicated in negative feedback control of NF-κB-driven inflammatory processes. We applied chromatin immunoprecipitation and reporter analysis to show that GR and NF-κB directly regulate A20 expression in HASM through cooperative induction of an intronic enhancer. Using overexpression, we show for the first time that A20 and its interacting partner, TNIP1, repress TNF signaling in HASM cells. Moreover, we applied small interfering RNA-based gene knockdown to demonstrate that A20 is required for maximal cytokine repression by GCs in HASM. Taken together, our data suggest that inductive regulation of A20 by GR and NF-κB contributes to cytokine repression in HASM.

scholarly journals Molecular Mechanisms for the Mechanical Modulation of Airway Responsiveness

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Wenwu Zhang ◽  
Susan J. Gunst
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Airway Responsiveness ◽  
Small Gtpase ◽  
Cortical Actin

The smooth muscle of the airways is exposed to continuously changing mechanical forces during normal breathing. The mechanical oscillations that occur during breathing have profound effects on airway tone and airway responsiveness both in experimental animals and humans in vivo and in isolated airway tissues in vitro. Experimental evidence suggests that alterations in the contractile and mechanical properties of airway smooth muscle tissues caused by mechanical perturbations result from adaptive changes in the organization of the cytoskeletal architecture of the smooth muscle cell. The cytoskeleton is a dynamic structure that undergoes rapid reorganization in response to external mechanical and pharmacologic stimuli. Contractile stimulation initiates the assembly of cytoskeletal/extracellular matrix adhesion complex proteins into large macromolecular signaling complexes (adhesomes) that undergo activation to mediate the polymerization and reorganization of a submembranous network of actin filaments at the cortex of the cell. Cortical actin polymerization is catalyzed by Neuronal-Wiskott–Aldrich syndrome protein (N-WASP) and the Arp2/3 complex, which are activated by pathways regulated by paxillin and the small GTPase, cdc42. These processes create a strong and rigid cytoskeletal framework that may serve to strengthen the membrane for the transmission of force generated by the contractile apparatus to the extracellular matrix, and to enable the adaptation of smooth muscle cells to mechanical stresses. This model for the regulation of airway smooth muscle function can provide novel perspectives to explain the normal physiologic behavior of the airways and pathophysiologic properties of the airways in asthma.

Endothelins and pulmonary diseases

1994 ◽  
Vol 77 (3) ◽  
pp. 1051-1059 ◽  
Author(s):  
P. J. Barnes
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Vascular Endothelial Cells ◽  
Airway Epithelial Cells ◽  
Pulmonary Diseases ◽  
Airway Epithelial ◽  
Airway Function ◽  
Type Ii Pneumocytes ◽  
Plasma Exudation ◽  
Submucosal Glands

Endothelins (ETs) are expressed in several types of cell in human lung, including airway epithelial cells, pulmonary vascular endothelial cells, submucosal glands, and type II pneumocytes. There is evidence for increased expression of ET-1 in several pulmonary diseases, including asthma, fibrosing alveolitis, and pulmonary hypertension, suggesting that ET-1 may play a pathophysiological role. ET binding sites are widely distributed and are localized to airway and pulmonary vascular smooth muscle, fibroblasts, submucosal glands, and airway nerves, indicating that ETs may have widespread effects. ET-1 and ET-3 are potent constrictors of human airway smooth muscle via a direct effect on ET receptors in airway smooth muscle; these receptors are probably ETB receptors. ETs may have other effects on airway function, including constriction of bronchial vessels, increased plasma exudation, increased mucus secretion, airway smooth muscle hyperplasia, and possibly increased fibrogenesis; these effects may be mediated via ETA receptors. ET-1 is a potent constrictor of human pulmonary vessels, whereas ET-3 is less effective, suggesting a predominance of ETA receptors. Similarly, chemotaxis and mitogenesis of pulmonary vascular fibroblasts and smooth muscle are mediated via ETA receptors. These findings implicate ETs in various pulmonary diseases and suggest that ET antagonists may be useful in their treatment.

Airway basement membrane perimeter distensibility and airway smooth muscle area in asthma

2008 ◽  
Vol 104 (6) ◽  
pp. 1703-1708 ◽  
Author(s):  
Alan L. James ◽  
Francis H. Green ◽  
Michael J. Abramson ◽  
Tony R. Bai ◽  
Marisa Dolhnikoff ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Basement Membrane ◽  
Airway Smooth Muscle ◽  
Muscle Area ◽  
Airway Collapse ◽  
Fatal Asthma ◽  
Regression Slopes ◽  
The Relationship ◽  
Asthma Group

The perimeter of the basement membrane (Pbm) of an airway viewed in cross section is used as a marker of airway size because in normal lungs it is relatively constant, despite variations in airway smooth muscle (ASM) shortening and airway collapse. In vitro studies (McParland BE, Pare PD, Johnson PR, Armour CL, Black JL. J Appl Physiol 97: 556-563, 2004; Noble PB, Sharma A, McFawn PK, Mitchell HW. J Appl Physiol 99: 2061-2066, 2005) have suggested that differential stretch of the Pbm between asthmatic and nonasthmatic airways fixed in inflation may occur and lead to an overestimation of ASM thickness in asthma. The relationships between the Pbm and the area of ASM were compared in transverse sections of airways from cases of fatal asthma (F) and from nonasthmatic control (C) cases where the lung tissue had been fixed inflated (Fi; Ci) or uninflated (Fu; Cu). When all available airways were used, the regression slopes were increased in Fu and Cu, compared with Fi and Ci, and increased in Fu and Fi, compared with Cu and Ci, suggesting effects of both inflation and asthma group, respectively. When analyses were limited to airway sizes that were available for all groups (Pbm < 15 mm), the slopes of Fi and Fu were similar, but both were greater than Ci and Cu, which were also similar. It was calculated that the effect of asthma group accounted for 80% and inflation for 20% of the differences between Fi and Ci. We conclude that the effects of inflation on the relationship between Pbm and ASM are small and do not account for the differences observed in ASM between cases of asthma and nonasthmatic controls.

scholarly journals Tea Polyphenols Selectively Inhibit Proliferation and Migration of Airway Smooth Muscle Cells

2018 ◽  
Vol 9 (2) ◽  
pp. 39
Author(s):  
Mengmeng Yang ◽  
Fang Liang ◽  
Defeng Xu ◽  
Yue Wang ◽  
Huan Zhou ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Nuclear Factor Κb ◽  
Tea Polyphenols ◽  
Airway Smooth Muscle Cells ◽  
And Migration ◽  
Dose Dependent

Airway smooth muscle cells (ASMCs) have been recommended as a target for the treatment of inflammation and narrowing of the airways in asthma. New safe and efficient approaches to relieve symptoms caused by ASMCs is highly desired. Inspired by the inhibitory effects of tea polyphenols on vascular smooth muscle cells (VSMCs), tea polyphenols were applied in the current work to evaluate their regulation of ASMCs in vitro. A dose-dependent decrease of ASMCs density was observed after 24 h incubation with tea polyphenols. Additionally, ASMCs were significantly more sensitive to tea polyphenols than human bronchial epithelial cells (HBECs). Tea polyphenol treatment led to a dose dependent inhibition on ASMC migration and reduced the gene expression of nuclear factor-κB (NF-κB). In studies which compared the four main polyphenolic constituents of tea polyphenols—including epicatechin (EC), epicatechingallate (ECG), epigallocatechin (EGC) and epigallocatechingallate (EGCG)—on the proliferation of ASMCs, EGC was identified as being the most potent. These results suggest tea polyphenols are a promising agent for ASMCs targeted asthma control.

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