cyclic-gmp and Pneumonia

Pulmonary arterial hypertension is a progressive, fatal disease. Current treatments including prostanoids, endothelin-1 (ET-1) antagonists, and phosphodiesterase (PDE) inhibitors, have sought to address the pulmonary vascular endothelial dysfunction and vasoconstriction associated with the condition. These treatments may slow the progression of the disease but do not afford a cure. Future treatments must target more directly the structural vascular changes that impair blood flow through the pulmonary circulation. Several novel therapeutic targets have been proposed and are under active investigation, including soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-HT2B receptors, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, Rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. Tyrosine kinase inhibitors, statins, 5-HT2B receptor antagonists, EPCs and soluble guanylyl cyclase activators are among the most advanced, having produced encouraging results in animal models, and human trials are underway. This review summarises the current research in this area and speculates on their likely success.

Topics: Adrenomedullin; Animals; Bone Morphogenetic Protein Receptors; Cyclic GMP; Dichloroacetic Acid; Drug Discovery; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; NFATC Transcription Factors; Pancreatic Elastase; Pneumonia; Receptor Protein-Tyrosine Kinases; rho-Associated Kinases; Serotonin; Stem Cells; Vasoactive Intestinal Peptide

Topics: Alternaria; Alternariosis; Animals; Cyclic GMP; Cytokines; Immunity, Innate; Inflammation; Lung; Membrane Proteins; Mice; Mice, Knockout; Pneumonia; Signal Transduction

Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.

Topics: Administration, Inhalation; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Cyclic GMP; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucocorticoids; Guanylate Cyclase; Hydrazines; Hydrocortisone; Injections, Intraperitoneal; Lipopolysaccharides; Methacholine Chloride; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Ovalbumin; Oxadiazoles; Pneumonia; Quinoxalines; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid; Respiration, Artificial; Respiratory Mechanics; Soluble Guanylyl Cyclase

Carbon monoxide (CO) in expired gas has been shown to be elevated with asthma; however, its function is not known, and there is some potential that it may serve a bronchoprotective role to decrease airway hyperresponsiveness (AHR). Thus the ability of CO to reverse methacholine (MCh)-induced bronchoconstriction was evaluated in C57BL/6 (C57) and A/J mice with and without airway inflammation produced by ovalbumin (OVA). Acutely administered CO (1% in air, 10 min) reduced MCh-driven increases in lung resistance in OVA-challenged C57 mice by an average of 50% (from 14.5 to 7.1 cmH2O.ml-1.s-1), whereas no effect was observed in naïve C57 mice or OVA-challenged C57 mice inhaling air alone. Acutely inhaled CO (500 ppm = 0.05%, for 10 min) reduced MCh-induced airway reactivity (AR) by 20-60% in airway hyperresponsive naïve A/J mice, whereas repeated 10-min administrations of 500 ppm CO over a 5-day period decreased AR by 50%. Repeated administration of low-dose CO [250 (0.025%) and (0.05%) 500 ppm, 1 h/day, 5 days] to A/J mice with airway inflammation likewise resulted in a drop of AR by 50%, compared with those not receiving CO. Inhibition of guanylyl cyclase/guanosine 3',5'-cyclic monophosphothioate (cGMP) using 1H-[1,2,4] oxydiazolo[4,3-a]quinoxalin-1-one or a competitive inhibitor, Rp diastereomers of 8-bromo-cGMP, resulted in inhibition of the effect of CO on AHR, suggesting that the effects of CO were mediated through this mechanism. These results indicate that low-dose CO can effectively reverse AHR in the presence and absence of airway inflammation in mice and suggest a potential role for CO in the modulation of AHR.

Topics: Airway Resistance; Animals; Bronchial Hyperreactivity; Bronchoconstriction; Carbon Monoxide; Cyclic GMP; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Muscle, Smooth; Pneumonia

Interleukin (IL)-11, like other members of the gp130 receptor class, possesses anti-inflammatory properties. We hypothesized that IL-11 pretreatment would attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammation and diminish injury to endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation that require cGMP in Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis factor (TNF)-alpha compared with the saline control (0.7 +/- 0.15 ng/g lung wet wt for control vs. 3.5 +/- 0.09 ng/g lung wet wt for LPS; P < 0.05). IL-11 (200 mg/kg ip) injected 10 min before LPS administration attenuated the LPS-induced lung TNF-alpha levels (1.6 +/- 0.91 ng/g lung wet wt; P < 0.05 vs. LPS). IL-11 also diminished LPS-induced lung neutrophil sequestration as assessed by myeloperoxidase units (2.1 +/- 0.25 U/g lung wet wt for saline and 15.6 +/- 2.02 U/g lung wet wt for LPS vs. 7.07 +/- 1.65 U/g lung wet wt for LPS plus IL-11; P < 0.05). Similarly, TNF-alpha binding protein (175 mg/kg) attenuated LPS-induced myeloperoxidase activity (6.04 +/- 0.14 U/g lung wet wt; P < 0.05). Both IL-11 and TNF-alpha binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to 10(-7) and 10(-6) M acetylcholine and A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings (P < 0.05 vs. LPS). Endothelium-independent relaxation responses to sodium nitroprusside were also improved after LPS at 10(-6) M (P < 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-induced mortality in CF1 mice from 90 to 50% (P

Topics: Acetylcholine; Animals; Antigens, CD; Calcimycin; Cyclic GMP; Cytokine Receptor gp130; Interleukin-11; Ionophores; Lipopolysaccharides; Lung; Male; Membrane Glycoproteins; Neutrophils; Nitroprusside; Peroxidase; Pneumonia; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Survival Analysis; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha; Vasodilator Agents

The results of clinical-roentgenological and hormonal-immunological studies showed that immunohomeostasis peculiarities and adaptation in children with thymomegaly and pneumonia-complicated thymomegaly are determined by prolonged 'metabolic stress' effect associated with thymomegaly and coexistent intercurrent infection. Immune control of children with thymomegaly is appreciably determined by the hormonal function of hypothalamus-hypophysis-thymus-adrenal cortex system and by optimum balance of its constituents. Hypothalamic-hypophysial-adrenal system, cAMP and cGMP as universal intracellular mediators, and, essentially, thymus hormonal function are basic contributors to immunohomeostatis and adaptive reaction control in children with thymomegaly.

Topics: Adrenocorticotropic Hormone; B-Lymphocytes; Child, Preschool; Cyclic AMP; Cyclic GMP; Female; Humans; Hydrocortisone; Immunologic Deficiency Syndromes; Infant; Lymphatic Diseases; Male; Pneumonia; T-Lymphocytes; Thymus Gland

The patients with acute pneumonias demonstrated interdependent changes in lipid peroxidation (LPO), antioxidant system (AOS), immune system (IS), and in the pituitary-adrenocortical system (PAS), related to the character of the disease course. The most pronounced changes were seen in the patients with acute pneumonias eventuating in pneumofibrosis. The high level of LPO was combined with AOS depletion, immunodeficiency formation, and with dysfunction of the PAS. Antibacterial treatment did not exert any appreciable effect on the characteristics under study. Thus, the level of LPO and AOS status are important components in the pathogenesis of acute pneumonias, determining the character of the disease course and outcome. It is advisable that research work aimed at the design of the principles of antioxidant therapy may be intensified.

Topics: Acute Disease; Adrenocorticotropic Hormone; Antioxidants; Cyclic AMP; Cyclic GMP; Humans; Hydrocortisone; Lipid Peroxidation; Pneumonia

Topics: Adolescent; Adult; Aged; Catecholamines; Coronary Disease; Cyclic AMP; Cyclic GMP; Female; Humans; Hypertension; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged; Pneumonia

Topics: Asthma; Child, Preschool; Chronic Disease; Cyclic AMP; Cyclic GMP; Humans; Leukocytes; Pneumonia

Topics: Adolescent; Adult; Aged; Asthma; Bronchitis; Cyclic AMP; Cyclic GMP; Female; Humans; Leukocytes; Lipid Peroxides; Lung Diseases; Male; Middle Aged; Pneumonia

Topics: Acute Disease; Adult; Cyclic AMP; Cyclic GMP; Humans; Male; Middle Aged; Pneumonia