Muscarinic receptor signaling in the pathophysiology of asthma and COPD

Anticholinergics are widely used for the treatment of COPD, and to a lesser extent for asthma. Primarily used as bronchodilators, they reverse the action of vagally derived acetylcholine on airway smooth muscle contraction. Recent novel studies suggest that the effects of anticholinergics likely extend far beyond inducing bronchodilation, as the novel anticholinergic drug tiotropium bromide can effectively inhibit accelerated decline of lung function in COPD patients. Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle. Vagally derived acetylcholine also regulates mucus production in the airways. A number of recent research papers also indicate that acetylcholine, acting through muscarinic receptors, may in part regulate pathological changes associated with airway remodeling. Muscarinic receptor signalling regulates airway smooth muscle thickening and differentiation, both in vitro and in vivo. Furthermore, acetylcholine and its synthesizing enzyme, choline acetyl transferase (ChAT), are ubiquitously expressed throughout the airways. Most notably epithelial cells and inflammatory cells generate acetylcholine, and express functional muscarinic receptors. Interestingly, recent work indicates the expression and function of muscarinic receptors on neutrophils is increased in COPD. Considering the potential broad role for endogenous acetylcholine in airway biology, this review summarizes established and novel aspects of muscarinic receptor signaling in relation to the pathophysiology and treatment of asthma and COPD

Reply to:“Arginase inhibitors: An alternative in treatment of obese asthma?”

An alternative in treatment of obese asthma

The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

Background: Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established. Methods: Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro. Results: Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline-and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR. Conclusion: These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide

Role of contractile prostaglandins and Rho-kinase in growth factor-induced airway smooth muscle contraction

Background: In addition to their proliferative and differentiating effects, several growth factors are capable of inducing a sustained airway smooth muscle (ASM) contraction. These contractile effects were previously found to be dependent on Rho-kinase and have also been associated with the production of eicosanoids. However, the precise mechanisms underlying growth factor-induced contraction are still unknown. In this study we investigated the role of contractile prostaglandins and Rho-kinase in growth factor-induced ASM contraction.Methods: Growth factor-induced contractions of guinea pig open-ring tracheal preparations were studied by isometric tension measurements. The contribution of Rho-kinase, mitogen-activated protein kinase ( MAPK) and cyclooxygenase ( COX) to these reponses was established, using the inhibitors Y-27632 ( 1 mu M), U-0126 ( 3 mu M) and indomethacin ( 3 mu M), respectively. The Rho-kinase dependency of contractions induced by exogenously applied prostaglandin F-2 alpha (PGF(2 alpha)) and prostaglandin E-2 (PGE(2)) was also studied. In addition, the effects of the selective FP-receptor antagonist AL-8810 (10 mu M) and the selective EP1-antagonist AH-6809 (10 mu M) on growth factor-induced contractions were investigated, both in intact and epithelium-denuded preparations. Growth factor-induced PGF(2 alpha)- and PGE(2)-release in the absence and presence of Y-27632, U-0126 and indomethacin, was assessed by an ELISA-assay.Results: Epidermal growth factor (EGF)- and platelet-derived growth factor ( PDGF)- induced contractions of guinea pig tracheal smooth muscle preparations were dependent on Rho-kinase, MAPK and COX. Interestingly, growth factor-induced PGF(2 alpha)- and PGE(2)-release from tracheal rings was significantly reduced by U-0126 and indomethacin, but not by Y-27632. Also, PGF2a- and PGE(2)-induced ASM contractions were largely dependent on Rho-kinase, in contrast to other contractile agonists like histamine. The FP-receptor antagonist AL-8810 ( 10 mu M) significantly reduced ( approximately 50 %) and the EP1-antagonist AH-6809 ( 10 mu M) abrogated growth factor-induced contractions, similarly in intact and epithelium-denuded preparations.Conclusion: The results indicate that growth factors induce ASM contraction through contractile prostaglandins - not derived from the epithelium - which in turn rely on Rho-kinase for their contractile effects.</p

Causas de Morte em Doentes com Hemofilia: Estudo Retrospectivo de 1979 a 2007, no Serviço de Imunohemoterapia do HSJ

Neurokinin A (NKA) induces bronchoconstriction mediated by tachykinin NK2 receptors in animals and humans, and may be increased in asthma. Because beta(2)-adrenoceptor agonists are the most widely used bronchodilators in asthma, we investigated the effects of the beta(2)-adrenoceptor agonist fenoterol on NK2 receptor messenger RNA (mRNA) and receptor density as well as the functional responses of bovine tracheal smooth muscle to the NK2 receptor agonist [beta-Ala(8)]-NKA(4-10) in vitro, using Northern blot analysis, receptor binding, and organ bath studies. Incubation with fenoterol induced a time- and concentration-dependent upregulation of NK2 receptor mRNA (71% increase after 12 h at 10(-7) M fenoterol), which was abolished by propranolol (a nonselective beta-adrenoceptor agonist) and ICI118551 (a selective beta(2)-adrenoceptor antagonist), but not by CGP20712A (a selective beta(1)-adrenoceptor antagonist), indicating that fenoterol acts via beta(2)-adrenoceptors. These effects were mimicked by forskolin and prostaglandin E-2 (PGE,), both agents that increase cyclic adenosine monophosphate (cAMP), and by the cAMP analogue 8-bromo-cAMP. The upregulation was blocked by cycloheximide, indicating that it requires new protein synthesis, and was accompanied by an increase in both the stability of NK2 receptor mRNA and the rate of NK2 receptor gene transcription. Radioligand binding assay using the selective NK2 receptor antagonist [H-3]SR48968 showed a significant increase in the number of receptor binding sites after 12 h and 18 h, which was accompanied by an increased contractile responsiveness to the NK2 receptor agonist [beta-Ala(8)]-NKA(4-10). Dexamethasone completely prevented the fenoterol-induced increase in NK2 receptor mRNA and in the contractile response. We conclude that beta(2)-adrenoceptor agonists induce upregulation of functional NK2 receptors in airway smooth muscle by increasing cAMP, and that this can be prevented by a corticosteroid. The increased responsiveness could be relevant to asthma control and mortality

Arginine homeostasis in allergic asthma

Allergic asthma is a chronic disease characterized by early and late asthmatic reactions, airway hyperresponsiveness, airway inflammation and airway remodelling. Changes in L-arginine homeostasis may contribute to all these features of asthma by decreased nitric oxide (NO) production and increased formation of peroxynitrite, polyamines and L-proline. Intracellular L-arginine levels are regulated by at least three distinct mechanisms: (i) cellular uptake by cationic amino acid (CAT) transporters, (ii) metabolism by NO-synthase (NOS) and arginase, and (iii) recycling from L-citrulline. Ex vivo studies using animal models of allergic asthma have indicated that attenuated L-arginine bioavailability to NOS causes deficiency of bronchodilating NO and increased production of procontractile peroxynitrite, which importantly contribute to allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction, respectively. Decreased cellular uptake of L-arginine, due to (eosinophil-derived) polycations inhibiting CATs, as well as increased consumption by increased arginase activity are major causes of substrate limitation to NOS. Increasing substrate availability to NOS by administration Of L-arginine, L-citrulline, the polycation scavenger heparin, or an arginase inhibitor alleviates allergen-induced airway hyperresponsiveness by restoring the production of bronchodilating NO. In addition, reduced L-arginine levels may contribute to the airway inflammation associated with the development of airway hyperresponsiveness, which similarly may involve decreased NO synthesis and increased peroxynitrite formation. Increased arginase activity could also contribute to airway remodelling and persistent airway hyperresponsiveness in chronic asthma via increased synthesis of L-ornithine, the precursor of polyamines and L-proline. Drugs that increase the bioavailability of L-arginine in the airways - particularly arginase inhibitors - may have therapeutic potential in allergic asthma. (C) 2008 Elsevier B.V. All rights reserved