Abstract
BackgroundAirway remodelling is the major pathological feature of chronic obstructive pulmonary disease (COPD), and leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective in controlling airway remodelling. In the present study, we investigated the potential role of artesunate in preventing and treating airway remodelling and the underlying molecular mechanisms in vitro and in vivo.MethodsA COPD rat model was established by cigarette smoke (CS) exposure. After 12 weeks of artesunate treatment, pathological changes in the lung tissues of COPD rats were examined by ELISA and histochemical and immunohistochemical staining. A lung functional experiment was also carried out to elucidate the effects of artesunate. Human bronchial smooth muscle (HBSM) cells were used to clarify the underlying molecular mechanisms.ResultsArtesunate treatment inhibited CS-induced airway inflammation and oxidative stress in a dose-dependent manner and significantly reduced airway remodelling by inhibiting α-smooth muscle actin (α-SMA) and cyclin D1 expression. PPAR-γ was upregulated and TGF-β1/Smad2/3 signalling was inactivated by artesunate treatment in vivo and in vitro. Furthermore, PPAR-γ knockdown by siRNA transfection abolished artesunate-mediated inhibition of HBSM cell proliferation by activiting the TGF-β1/Smad2/3 signalling pathway and downregulating the expression of α-SMA and cyclin D1 in HBSM cells.ConclusionsThese findings suggest that artesunate could be used to treat airway remodelling by regulating PPAR-γ/TGF-β1/Smad signalling in the context of COPD.
Highlights
Airway remodelling is a major pathological abnormality in chronic obstructive pulmonary disease (COPD) [1]
Role of artesunate in reducing airway inflammation and oxidative stress in the lungs of cigarette smoke (CS)‐exposed rats IL-6, IL-8, Tumor necrosis factor alpha (TNF-α), and Intercellular adhesion molecule 1 (ICAM-1), which amplify the inflammatory process and induce airway structural changes were examined in Bronchoalveolar lavage fluid (BALF) after 12 weeks of CS exposure
(See figure on page.) Fig. 2 Artesunate attenuated CS-induced airway remodelling in rats. a Masson’s trichrome staining was performed to determine airway histopathological changes. b–d The airway fibrosis, airway epithelial thickness and airway smooth muscle thickness were quantified by Image J. e–h Immunohistochemical staining were performed to determine α-smooth muscle actin (α-SMA) and cyclin D1 expressions in the lungs. i, j The proteins levels of α-SMA and cyclin D1 in the lungs were analyzed by Western blot
Summary
Airway remodelling is a major pathological abnormality in chronic obstructive pulmonary disease (COPD) [1]. Increasing evidence has revealed that PPAR-γ agonists can inhibit the proliferation of human airway smooth muscle cells, and reduce inflammatory cell infiltration and airway remodelling by activating PPAR-γ in the context of COPD [7,8,9]. Targeting PPAR-γ signalling could represent an effective strategy for the preventingand treating airway remodelling in COPD. Artesunate could inhibit the proliferation of primary human cultured airway smooth muscle cells [19, 20] and improve bleomycin-induced pulmonary fibrosis pathology in rats by inhibiting TGF-β1–Smad activation [21]. We investigated the potential role of artesunate in preventing and treating airway remodelling and the underlying molecular mechanisms in vitro and in vivo
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