cyclic-gmp and Pulmonary-Disease--Chronic-Obstructive

Nitric oxide (NO) is a gaseotransmitter, which is involved in many signaling processes in health and disease. Three enzymes generate NO from l-arginine, with citrulline formed as a by-product: neuronal NO synthase (nNOS or NOS1), endothelial NOS (eNOS or NOS3) and inducible NOS (iNOS or NOS2). NO is a ligand of soluble guanylyl cyclase (sGC), an intracellular heterodimer enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP). cGMP further activates protein kinase G that eventually reduces the smooth muscle tone in bronchi or vessels. Phosphodiesterase 5 (PDE5) degrades cGMP to GMP. However, NO reacts with superoxide anion (O2(-)), leading to formation of the pro-inflammatory molecule peroxynitrite. Under physiological conditions, NO plays a homeostatic bronchoprotective role in healthy subjects. In obstructive airway diseases, NO can be beneficial by its bronchodilating effect, but could also be detrimental by the formation of peroxynitrite. Since asthma and COPD are associated with increased levels of exhaled NO, chronic inflammation and increased airway smooth muscle tone, the NO/sGC/cGMP pathway could be involved in these highly prevalent obstructive airway diseases. Here we review the involvement of NO, NO synthases, guanylyl cyclases, cGMP and phophodiesterase-5 in asthma and COPD and potential therapeutic approaches to modulate this pathway.

Topics: Animals; Asthma; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanylate Cyclase; Humans; Nitric Oxide; Nitric Oxide Synthase; Pulmonary Disease, Chronic Obstructive; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Superoxides

Topics: Aminopyridines; Anti-Inflammatory Agents; Benzamides; Cilia; Cyclic AMP; Cyclic GMP; Cyclopropanes; Humans; Inflammation; Isoenzymes; Mucins; Oxidative Stress; Phosphodiesterase 4 Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Circulation; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Second Messenger Systems

In order to measure the plasma levels of interleukin-4 (IL-4), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in patients with chronic obstructive pulmonary disease (COPD) and observe the effects of oral theophylline on them, we divided 28 COPD patients into COPD experimental group and COPD control group. Plasma levels of IL-4, cAMP and cGMP as well as parameters of pulmonary function tests were measured in these 2 groups before and after 2 weeks of treatment with oral theophylline (Protheo, 400 mg, qd) or placebo. Plasma levels of IL-4 and cGMP were significantly elevated in patients with COPD as compared with normal controls (P < 0.05), while cAMP and cAMP/cGMP were significantly lower than those in controls (P < 0.01). Plasma level of IL-4 was inversely correlated with forced expiratory volume at the first second (FEV1) and with maximum expiratory flow rate at 50% of forced vital capacity (V50) (both r = -0.46, P < 0.05) while it was directly correlated with the scores of the clinical manifestations (r = 0.57, P < 0.05) in COPD patients. Two weeks after treatment with theophylline, IL-4 and cGMP in COPD experimental group were decreased significantly while cAMP and cAMP/cGMP increased significantly (P < 0.05). The change of IL-4 was inversely correlated with the changes of FEV1 and V50 (r = -0.53 and -0.54, respectively, P < 0.05). Two weeks after placebo treatment, the COPD control group did not show such changes. We are led to conclude that IL-4 might play a role in the pathogenesis of the airway inflammation and air flow limitation in COPD patients and the mechanisms of theophylline's therapeutic effects of attenuating air-flow limitation may partially depend on its anti-inflammatory effects on the airways which, in turn, is dependent on its inhibitory effects on some inflammatory mediators such as IL-4.

Topics: Aged; Bronchodilator Agents; Cyclic AMP; Cyclic GMP; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Interleukin-4; Male; Maximal Expiratory Flow Rate; Middle Aged; Pulmonary Disease, Chronic Obstructive; Theophylline

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways,

Topics: Animals; Cyclic GMP; Disease Models, Animal; Humans; Hypertension, Pulmonary; Lung; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pyrazoles; Pyrimidines; Retrospective Studies; Signal Transduction; Soluble Guanylyl Cyclase; Translational Research, Biomedical

Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both.. C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted.. Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages.. Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice.

Topics: Animals; Benzamides; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Hypertension, Pulmonary; Lung; Lung Compliance; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase 4 Inhibitors; Phosphodiesterase 5 Inhibitors; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pyridines; Smoke; Smoking; Tadalafil

It has recently been shown that systemic endothelial dysfunction is associated with airflow limitation in COPD. We conducted this ex vivo study to assess whether endothelial dysfunction of pulmonary arteries of former smokers was associated with modifications of airway functions.. Pharmacological experiments were conducted on arterial and bronchial rings obtained from lung specimen of 20 patients: 13 smokers without COPD and 7 smokers with mild to moderate COPD (GOLD class I or II). The impairment of acetylcholine-mediated vasodilation (constriction) of preconstricted arterial rings defined endothelial dysfunction. Resting tone (initial and after a contraction test) and cGMP-mediated dilation of bronchial rings in response to zaprinast were evaluated.. Initial airway resting tone was correlated with airflow limitation (FEV(1) % predicted: Rho = -0.49; p = 0.032). The acetylcholine response of arterial rings was correlated with zaprinast-induced bronchodilation (Rho = 0.54, p = 0.019). Patients with endothelial dysfunction (n = 5), as compared with those displaying no dysfunction (n = 15), were characterized by an increased resting tone (after contraction test), an impaired response to zaprinast but a similar degree of airflow limitation (FEV(1)).. Endothelial dysfunction of pulmonary arteries is associated with increased resting tone and impaired cGMP-mediated dilation of airways in former smokers, suggesting common underlying mechanisms of pulmonary arterial and bronchial dysfunctions.

Topics: Acetylcholine; Aged; Bronchi; Bronchodilator Agents; Cyclic GMP; Endothelium, Vascular; Female; Forced Expiratory Volume; Humans; In Vitro Techniques; Male; Middle Aged; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Purinones; Smoking; Vasodilation