The Role of Chlorpromazine in the Treatment of Bronchial Asthma and Chronic Pulmonary Emphysema

Baum, Gerald L.; Schotz, Sylvan A.; Gumpel, Roy C.; Osgood, Catherine

doi:10.1378/chest.32.5.574

Cited by 6 publications

(1 citation statement)

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“…Together with observations of NOX‐selective actions of other phenothiazines (Gianni et al ., ; Seredenina et al ., ), these findings suggest opportunities for development of DUOX1‐selective inhibitors based on phenothiazine scaffolds. In fact, previous uses of phenothiazine‐based compounds such as CPZ or structurally similar compounds for the treatment of allergic disease (Baum et al ., ) might have been related in part to their ability to inhibit DUOX1.…”

Section: The Search For Nox‐selective Inhibitorsmentioning

confidence: 99%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. AbbreviationsCPZ, chlorpromazine; DPI, diphenylene iodonium; DUOX, dual oxidase; DUOXA, dual oxidase maturation factor; EGFR, EGF receptor; ER, endoplasmic reticulum; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LPO, lactoperoxidase; MPO, myeloperoxidase; NOX, NADPH oxidase; NOXA, NOX activator; PDB, protein database; PHD, peroxidase homology domain; ROS, reactive oxygen species; TK, tyrosine kinase; TLR, toll-like receptor; TPO, thyroperoxidase; TRX, thioredoxin IntroductionThe concept of oxidative stress has been widely embraced as a major factor in disease pathology and has fuelled a billion dollar industry based on antioxidant dietary supplements. However, clinical studies using antioxidant supplementation strategies have generally been unsuccessful in attenuating disease risk or progression, and antioxidant supplementation was in some cases found to even worsen pathological outcomes (Ghezzi et al., 2017). This lack of success likely relates to the flawed concept of oxidative stress as a pharmacological target. First, oxidative stress can be brought about by a range of ROS (the commonly used acronym to define this group of reactive metabolites), which can originate from external sources (e.g. environmental pollution and metabolism of xenobiotics) or be generated endogenously by various enzymatic systems, in some cases in a regulated and deliberate fashion to serve important biological functions [e.g. by activation of NADPH oxidases (NOXs)]. Therefore, generic non-selective approaches that indiscriminately suppress ROS may not have the desired outcome. A second flaw with such generic antioxidant approaches is the fact that ROS represent a diverse group of reactive metabolites that each have unique (bio)chemical properties, and it is often unclear to what extent antioxidant supplements counter the action of individual ROS species. To clarify this, it is helpful to distinguish primary from secondary ROS, with primary ROS representing the initial products of (enzymatic) O 2 reduction [i.e. superoxi...

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Section: The Search For Nox‐selective Inhibitorsmentioning

confidence: 99%