Airway smooth muscle: A modulator of airway remodeling in asthma

Lazaar, Aili L.; Panettieri, Reynold A.

doi:10.1016/j.jaci.2005.06.030

Cited by 126 publications

(96 citation statements)

References 85 publications

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“…In addition to fibrosis, enhanced deposition of extracellular matrix protein, epithelial injury, and airway smooth muscle hypertrophy, airway smooth muscle cell division/proliferation significantly contributes to the pathogenesis of airway remodeling (27)(28)(29)(30). Our recent studies suggest that c-Abl is up-regulated in asthmatic cells (13).…”

Section: Discussionmentioning

confidence: 97%

c-Abl Tyrosine Kinase Regulates Cytokinesis of Human Airway Smooth Muscle Cells

Chen

Tang

2014

Am J Respir Cell Mol Biol

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Cytokinesis is a critical step of airway smooth muscle cell division that plays an essential role in the development and homeostasis of the respiratory system, as well as the progression of airway remodeling. The mechanisms that regulate smooth muscle cytokinesis are not fully understood. c-Abl (c-Abelson tyrosine kinase) is a nonreceptor protein tyrosine kinase that has a role in regulating actin dynamics and smooth muscle contraction. The role of c-Abl in cytokinesis has not been investigated. Here, c-Abl was found in the contractile ring, as evidenced by immunofluorescent microscopy. In addition, cortactin is a phosphorylatable protein that has been implicated in actin filament assembly. In this report, phosphorylated cortactin was also found in the contractile ring. Knockdown of c-Abl by RNA interference attenuated cortactin phosphorylation in the midzone and contractile ring formation. c-Abl knockdown decreased the number of cells undergoing cytokinesis, but increased the quantity of cells in metaphase/anaphase and the number of multinucleate cells. Treatment with the c-Abl pharmacological inhibitors, imatinib and GNF-5, had similar effects. Furthermore, the expression of a nonphosphorylatable cortactin mutant diminished cytokinesis. Finally, inhibition of actin filament assembly by latrunculin A attenuated c-Abl recruitment to the midzone. Thus, we propose a novel mechanism that regulates smooth muscle cell cytokinesis. c-Abl is recruited to the equator during cytokinesis, which may mediate cortactin phosphorylation. Phosphorylated cortactin may promote actin filament assembly, which facilitates contractile ring formation and cytokinesis. In addition, actin filament polymerization may facilitate the positioning of c-Abl to the contractile ring.

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Section: Discussionmentioning

confidence: 97%

c-Abl Tyrosine Kinase Regulates Cytokinesis of Human Airway Smooth Muscle Cells

Chen

Tang

2014

Am J Respir Cell Mol Biol

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“…This led to the finding that when primary cultures of ASM cells were treated in vitro with proinflammatory stimulants (such as TNF-␣), they secreted numerous cell adhesion molecules and cytokines (17), including IL-6 (2,22). IL-6 has many proinflammatory functions relevant to inflammation in asthma, and our in vitro investigations using primary cultures of ASM cells stimulated with TNF-␣ have allowed us to delineate many of the molecular mechanisms responsible for IL-6 cytokine secretion in this pivotal immunomodulatory cell type.…”

Section: Discussionmentioning

confidence: 99%

“…Since that time, the role of TTP in inflammatory conditions, such as arthritis, has become firmly established, while its impact on regulation of asthmatic inflammation is relatively underexplored. We address this herein by using human airway smooth muscle (ASM), a cell type characterized as having an important immunomodulatory role perpetuating airway inflammation through the secretion of various proinflammatory cytokines, including IL-6 (17). We are the first to investigate the role and function of TTP in this pivotal airway cell type in asthmatic inflammation.…”

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confidence: 99%

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1

Prabhala

Bunge

Rahman

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Prabhala P, Bunge K, Rahman MM, Ge Q, Clark AR, Ammit AJ. Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1. Am J Physiol Lung Cell Mol Physiol 308: L973-L980, 2015. First published February 27, 2015 doi:10.1152/ajplung.00219.2014.-Cytokines drive many inflammatory diseases, including asthma. Understanding the molecular mechanisms responsible for cytokine secretion will allow us to develop novel strategies to repress inflammation in the future. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study, we investigate the p38 MAPKmediated regulatory interaction of two anti-inflammatory proteins, mitogen-activated protein kinase phosphatase 1 (MKP-1) and tristetraprolin (TTP), in the context of asthmatic inflammation. Using primary cultures of airway smooth muscle cells in vitro, we explored the temporal regulation of IL-6 cytokine mRNA expression upon stimulation with TNF-␣. Intriguingly, the temporal profile of mRNA expression was biphasic. This was not due to COX-2-derived prostanoid upregulation, increased expression of NLRP3 inflammasome components, or upregulation of the cognate receptor for TNF-␣-TNFR1. Rather, the biphasic nature of TNF-␣-induced IL-6 mRNA expression was regulated temporally by the RNA-destabilizing molecule, TTP. Importantly, TTP function is controlled by p38 MAPK, and our study reveals that its expression in airway smooth muscle cells is p38 MAPK-dependent and its anti-inflammatory activity is also controlled by p38 MAPK-mediated phosphorylation. MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally distinct manner, MKP-1 ensures that TTP is expressed and made functional at precisely the correct time to repress cytokine expression. Together, p38 MAPK, MKP-1, and TTP may form a regulatory network that exerts significant control on cytokine secretion in proasthmatic inflammation through precise temporal signaling. p38 MAPK; tristetraprolin; MKP-1; inflammation; IL-6 MANY CHRONIC INFLAMMATORY diseases are a common consequence of overactive inflammatory signaling pathways. Hence, using these pathways as potential drug targets represents a way to re-establish control and attenuate the severity of such chronic inflammatory diseases. Asthma is a chronic inflammatory disease, which is characterized by reversible airway obstruction, structural remodeling, and airway hyperresponsiveness. A plethora of proinflammatory cytokines have been implicated in the pathophysiology of asthma. The common therapies for asthma include glucocorticoids and ␤ 2 -agonists; however, there is still a proportion of the population for which this treatment is ineffective. Hence, a need has arisen to find alternative anti-inflammatory strategies, such as using smallmolecule inhibitors of inflammatory cascades or using agents that could increase activity of anti-inflammatory proteins. To achieve this goal, a greater understanding of the regulatory networks that control cytokines are u...

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“…It is now well established that there is extensive airway remodeling that occurs in diseases such as asthma (11,22,113,169,190,285,302,333,337,348). Such remodeling is characterized by structural changes including a thickened abnormal epithelium with mucus gland hypertrophy, subepithelial membrane thickening, and fibrosis with altered ECM composition and deposition, angiogenesis, and importantly increased ASM mass (Fig.…”

Section: Asm In Airway Remodelingmentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

179

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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Airway smooth muscle: A modulator of airway remodeling in asthma

Cited by 126 publications

References 85 publications

c-Abl Tyrosine Kinase Regulates Cytokinesis of Human Airway Smooth Muscle Cells

c-Abl Tyrosine Kinase Regulates Cytokinesis of Human Airway Smooth Muscle Cells

Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

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