- 期刊
Long-Acting Beta-2 Agonist and Theophylline Attenuate Cigarette Smoke-Induced Airway Inflammation through Regulation of Cyclic Adenosine Monophosphate
摘要
Introduction: Adding theophylline, a non-selective phosphodiesterase (PDE) inhibitor, to a long-acting beta-2 agonist (LABA) provides an additive bronchodilation effect through preventing cyclic adenosine monophosphate (cAMP) degradation. This procedure has become a common therapeutic choice in the management of chronic obstructive pulmonary disease patients. Emerging studies have shown that the use of a LABA and PDE inhibitor may inhibit airway inflammation, but details of the mechanism require further investigation. Methods: Mice were exposed to cigarette smoke (CS) for 4 weeks to induce airway inflammation. Indacaterol maleate (IND, a LABA), theophylline, and their combination or a vehicle was given through intraperitoneal injection daily during the 4-week exposure. In addition, human primary bronchial epithelial cells (PBECs) were exposed to cigarette smoke extract (CSE) with or without treatment of IND or theophylline. Interleukin (IL)-8 production and the cAMP level in PBECs were measured. Inhibitors of downstream signaling, including adenylyl cyclase (AC) and protein kinase A (PKA), were used to evaluate the underlying mechanism. Results: IND, theophylline and their combination reduced CS-induced protein leakage and inflammatory cells accumulation in the bronchoalveolar lavage fluid, as well as lung inflammation and peribronchial collagen deposition in lung sections. IND and theophylline consistently inhibited CSE-induced increases in IL-8 production in PBECs through maintaining the cAMP level. This anti-inflammatory effect was alleviated by adding AC or PKA inhibitor. Conclusion: Both LABA and theophylline exert a potent inhibitory effect on CS-induced airway inflammation through regulating cAMP and the AC-PKA pathway.
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