RESUMEN
ß2-adrenergic receptor (ß2AR) agonists are the clinical gold standard for treatment and prophylaxis of airway constriction in pulmonary obstructive diseases such as asthma and COPD. Inhaled ß2-agonists elicit rapid bronchorelaxation of the airway smooth muscle, yet, clinical tachyphylaxis to this response can occur over repeated and chronic use, which reduces the bronchodilatory effectiveness. Several mechanisms have been proposed to impart ß2-agonist tachyphylaxis, most notably ß2AR desensitization. However, airway tissue is known to be highly oxidative, particularly in obstructive disease states where reactive oxygen species (ROS) generation is upregulated and ROS degradation is suboptimal yielding a large oxidative burden. Recent evidence demonstrates that ß2AR can regulate ROS generation and that ROS can post-translationally alter ß2AR cysteine residues via oxidation, leading to distinct functional receptor outcomes. Herein, we discuss the growing evidence for ß2AR mediated ROS generation in airway cells and the role of ROS in regulating ß2AR via cysteine-oxidation of the receptor. Given the functional consequence of the ß2AR-ROS signaling axis in the airways, we also discuss the potential role of ROS in mediating ß2-agonist tachyphylaxis.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Oxidación-Reducción , Especies Reactivas de Oxígeno , Receptores Adrenérgicos beta 2 , Taquifilaxis , Humanos , Especies Reactivas de Oxígeno/metabolismo , Oxidación-Reducción/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Receptores Adrenérgicos beta 2/metabolismo , Animales , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológicoRESUMEN
Asthma and other airway obstructive disorders are characterized by heightened inflammation and excessive airway epithelial cell reactive oxygen species (ROS), which give rise to a highly oxidative environment. After decades of use, ß2-adrenergic receptor (ß2AR) agonists remain at the forefront of treatment options for asthma, however, chronic use of ß2-agonists leads to tachyphylaxis to the bronchorelaxant effects, a phenomenon that remains mechanistically unexplained. We have previously demonstrated that ß2AR agonism increases ROS generation in airway epithelial cells, which upholds proper receptor function via feedback oxidation of ß2AR cysteine thiolates to Cys-S-sulfenic acids (Cys-SOH). Our previous results also demonstrate that prevention of normal redox cycling of this post-translational oxi-modification back to the thiol prevents proper receptor function. Given that Cys-S-sulfenic acids can be irreversibly overoxidized to Cys-S-sulfinic (Cys-SO2H) or S-sulfonic (Cys-SO3H) acids, which are incapable of further participation in redox reactions, we hypothesized that ß2-agonist tachyphylaxis may be explained by hyperoxidation of ß2AR to S-sulfinic acids. Here, using airway epithelial cell lines and primary small airway epithelial cells from healthy and asthma-diseased donors, we show that ß2AR agonism generates H2O2 in a receptor and NAPDH oxidase-dependent manner. We also demonstrate that acute and chronic receptor agonism can facilitate ß2AR S-sulfination, and that millimolar H2O2 concentrations are deleterious to ß2AR-mediated cAMP formation, an effect that can be rescued to a degree in the presence of the cysteine-donating antioxidant N-acetyl-L-cysteine. Our results reveal that the oxidative state of ß2AR may contribute to receptor functionality and may, at least in part, explain ß2-agonist tachyphylaxis.
Asunto(s)
Asma , Peróxido de Hidrógeno , Humanos , Peróxido de Hidrógeno/metabolismo , Ácidos Sulfénicos/metabolismo , Cisteína/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Taquifilaxis , Asma/metabolismo , Células Epiteliales/metabolismo , Receptores Adrenérgicos/metabolismoRESUMEN
Short-chain fatty acids (SCFAs) are biosynthesized via fermentation of polysaccharides by gastrointestinal microbiota and have been shown to have wide-reaching effects on almost all tissues, including the pancreatic islets. Historically, the effects of SCFAs have been attributed to their intracellular metabolism and function as energy sources, but the discovery of free fatty acid G protein-coupled receptors (GPCRs) in the 2000s suggested that many functional outcomes of SCFAs are receptor-mediated. The SCFA receptors FFA2/GPR43 and FFA3/GPR41 are expressed on ß-cells, where they regulate glucose-dependent insulin secretion, making them attractive targets for treatment of diabetes and other metabolic disorders. Here, we provide an update on the current evidence regarding regulation of FFA2/FFA3 receptors by specific probiotic bacterial species within the gut microbiome that synthesize SCFAs. We also review the body of research regarding the FFA2- and FFA3 receptor-specific function of SCFAs on ß-cells and discuss the somewhat controversial and opposing findings within these studies.