Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones

Abstract

Despite over 50 years of inhaled beta-agonists and corticosteroids as the default management or rescue drugs for asthma, recent research suggests that new therapeutic options are likely to emerge. This belief stems from both an improved understanding of what causes and regulates airway smooth muscle (ASM) contraction, and the identification of new targets whose inhibition or activation can relax ASM. In this review we discuss the recent findings that provide new insight into ASM contractile regulation, a revolution in pharmacology that identifies new ways to “tune” G protein-coupled receptors to improve therapeutic efficacy, and the discovery of several novel targets/approaches capable of effecting bronchoprotection or bronchodilation.

Tumor Necrosis Factor-α in Heart Failure: an Updated Review

“…Despite the knowledge that TNFα drives negative inotropy through βARs, less has been known on whether traditional pathways that mediate βAR dysfunction are engaged by the TNFα-driven mechanisms. Sympathetic hormones (catecholamines) mediate cardiac contractility through βARs 24, 124 . Diminution in βAR signaling to catecholamines occurs through βAR desensitization contributing to the pathogenesis of heart failure.…”

β2-Adrenoceptor Function in Asthma

“…β2-agonists act on the β2-adrenoceptor which activates adenylyl cyclase via the stimulatory G-protein Gs, resulting in cyclic adenosine mono-phosphosphate (cAMP) production and protein kinase A (PKA) activation which has been described as the main mechanism driving relaxation of airway smooth muscle. The relaxant pathways are multiple and include a inhibition of the myosin light chain kinase (MCLK) activity leading to a reduction of calcium sensitivity of the contractile proteins, modulation of intracellular calcium levels through the blockade of calcium release from intracellular stores, and induction of membrane hyperpolarization through activation of large-conductance calciumactivated potassium channels (BKca) (nicely reviewed in (Pera & Penn, 2016) and (Giembycz & Newton, 2006)). Inhibition of Rho pathways via the activation of cAMP-mediated exchange protein (Epac) has been also described as a mechanism for the beneficial effect of β2-agonists in ASM cells (Fogli et al, 2015).…”

Proinflammatory Cytokines Mediate GPCR Dysfunction

“…βARs are one of the most powerful regulators of cardiac contractility and lung relaxation function 205, 227 . Diminished response of βAR signaling to catecholamines (sympathetic hormones) occurs through a process defined as βAR desensitization that contributes to the pathogenesis of heart failure and potentially to asthma exacerbation.…”