Treatment of airway mucus hypersecretion.
Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, ss2-adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium-activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti-myristoylated alanine-rich C kinase substrate (MARCKS), peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen-activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal-regulated kinase (MEK/ERK), inhibitors, human calcium-activated chloride (hCACL2), channel blockers and retinoic acid receptor-a antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.
Section of Airway Disease, National Heart & Lung Institute, Imperial College London, UK. duncan.rogers@imperial.ac.uk
Duncan F
DF
Rogers
Peter J
PJ
Barnes
D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D029481:Bronchitis, Chronic / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D055271:Mucin 5AC; D009077:Mucins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009093:Mucus / Q000737:chemistry / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D018377:Neurotransmitter Agents / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D058473:Receptors, Purinergic P2Y2; D019141:Respiratory System Agents / Q000627:therapeutic use*
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C524678:MUC5AC protein, human; D008565:Membrane Proteins; D055271:Mucin 5AC; D009077:Mucins; D018377:Neurotransmitter Agents; C546385:P2RY2 protein, human; D011480:Protease Inhibitors; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D058473:Receptors, Purinergic P2Y2; D019141:Respiratory System Agents; D000076250:Myristoylated Alanine-Rich C Kinase Substrate