Abstract
BackgroundAirway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma.ObjectivesTo examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo.MethodsCellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma.ResultsActivation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance.ConclusionTSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling.
Highlights
Asthma is characterized by chronic inflammation and structural alterations in the airways [1] and airway remodeling is a common feature of asthma [2]
It is not surprising that cellular senescence is induced in airway epithelia of asthma
Previous reports have demonstrated the critical role of cellular senescence in chronic obstructive pulmonary disease (COPD) and other respiratory diseases, such as pulmonary fibrosis and lung cancer [44,45,46]
Summary
Asthma is characterized by chronic inflammation and structural alterations in the airways [1] and airway remodeling is a common feature of asthma [2]. Histological characteristics of airway remodeling include thickening of the lamina reticularis, epithelial shedding, subepithelial fibrosis, inflammatory cell infiltration, goblet cell hyperplasia, myofibroblast proliferation, smooth muscle hyperplasia and hypertrophy, and neovascularization of the airway wall [4] These features and airway hyper-responsiveness (AHR) are common in severe lung diseases such as asthma [5]. Airway epithelia produce some inflammatory factors that play critical roles in regulating metabolic and immunologic responses within airways These inflammatory factors are often involved in epithelial damage in patients with asthma [6]. Methods: Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling
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