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1.  Sustained Elevation of Systemic Oxidative Stress and Inflammation in Exacerbation and Remission of Asthma 
ISRN Allergy  2013;2013:561831.
Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro-MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management.
PMCID: PMC3773380  PMID: 24073339
2.  The Role of Circulating Serotonin in the Development of Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(2):e31617.
Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age.
The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA).
The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = −0.149, p = 0.108).
Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.
PMCID: PMC3272036  PMID: 22319639
3.  Postnatal changes in β-adrenoceptors in the lung and the effect of hypoxia induced pulmonary hypertension of the newborn 
British Journal of Pharmacology  2002;135(6):1415-1424.
β-adrenoceptor activation leads to pulmonary vasodilatation. The increase in circulating catecholamines at birth may assist the postnatal fall in vascular resistance by their activation. To study β1- and β2-adrenoceptors during postnatal adaptation, we used [125I]-iodocyanopindolol (ICYP) binding to lung membranes and sections to quantify and locate the binding sites in piglets from birth to 14 days of age and compared them with those in adult pigs. In addition, pulmonary hypertension was induced in newborn piglets by hypobaric hypoxia.In lung membranes the equilibrium dissociation constant (Kd) did not change with age for total β-adrenoceptors or for β2-adrenoceptors, but there was a significant increase in maximum binding sites (Bmax) between birth and 3 days of age. On tissue sections, Bmax increased between 3 days and adulthood with no change in Kd.Binding sites of β1- and β2-adrenoceptors were localized to the bronchial epithelium, to endothelium of extra- and intra-pulmonary arteries and to lung parenchyma. Total β-adrenoceptor density increased with age at all locations (P<0.05 – 0.01). At birth intrapulmonary arteries showed no binding, β2-adrenoceptors appeared on day 1 and increased up to 14 days of age. β1-adrenoceptors appeared by 3 days of age and increased with age.Hypobaric hypoxia from birth led to attenuation in the normal postnatal increase in receptor number, but hypoxia from 3 – 6 days did not decrease receptor density.The normal postnatal increase in β-adrenoceptors suggests a potential for catecholamine induced dilatation in the lung during adaptation which is attenuated in pulmonary hypertension.
PMCID: PMC1573262  PMID: 11906954
β-Adrenoceptors; lung development; hypobaric hypoxia; pulmonary arteries; ligand binding studies
4.  Glucocorticoids reverse IL-1β-induced impairment of β-adrenoceptor-mediated relaxation and up-regulation of G-protein-coupled receptor kinases 
British Journal of Pharmacology  2002;135(4):987-996.
The aim of the present study was to examine the effects of glucocorticoid dexamethasone on airway responsiveness to albuterol after intratracheal instillation of saline or IL-1β in Brown-Norway rats in vivo and to elucidate the molecular mechanism of this effect.IL-1β caused a significant reduction in albuterol-mediated relaxation to protect against MCh-induced bronchoconstriction. Dexamethasone attenuated the IL-1β-induced impaired relaxation while alone had no effect when compared to rats treated identically with saline.The density of β2-adrenoceptors was significantly reduced in lung membranes harvested from IL-1β-treated rats, which was associated with impaired isoproterenol- and forskolin-stimulated cyclic AMP accumulation and adenylyl cyclase (AC) activity ex vivo. Dexamethasone did not prevent IL-1β-induced down-regulation of β2-adrenoceptors but completely blocked IL-1β-induced impairment of cyclic AMP accumulation and AC activity stimulated by isoproterenol and forskolin.The inhibitory G-protein subtypes, Giα1, Giα2 and Giα3, were detected in lung membranes prepared from all groups of rats but the intensity of Giα1 and Giα2 was markedly increased in IL-1β-treated rats, which were not prevented by dexamethasone.The activity of cytosolic GRK and the expression of GRK2 and GRK5 were elevated in the lung of IL-1β-treated rats, which were completely abolished by dexamethasone.These results indicate that treatment of rats with IL-1β results in desensitization of pulmonary β2-adrenoceptors. In light of data obtained in this study, we propose that both the decrease in AC activity and the increase in GRK activity, which are reversed by dexamethasone, may underlie β2-adrenoceptor desensitization.
PMCID: PMC1573209  PMID: 11861327
Cytokines; β2-adrenoceptor; dexamethasone; adenylyl cyclase; G-protein; gene expression
5.  Chronic systemic administration of salmeterol to rats promotes pulmonary β2-adrenoceptor desensitization and down-regulation of Gsα 
British Journal of Pharmacology  2001;132(6):1261-1270.
The aim of the present study was to examine the effects of chronic infusion of the long-acting agonist salmeterol on pulmonary β2-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular basis of any altered state.Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E2 (PGE2), given acutely by the intravenous route, to protect against ACh-induced bronchoconstriction when compared to rats treated identically with vehicle.β1- and β2-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associated with impaired salmeterol- and PGE2-induced cyclic AMP accumulation ex vivo.Three variants of Gsα that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol.The activity of cytosolic, but not membrane-associated, G-protein receptor-coupled kinase was elevated in the lung of salmeterol-treated rats when compared to vehicle-treated animals.The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh-induced bronchoconstriction was short-acting (toff ∼45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation.These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary Gs-coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane-associated Gsα. The short-acting nature of salmeterol, when administered systemically, and the reduction in β-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective β-adrenoceptor agonist.
PMCID: PMC1572675  PMID: 11250877
β2-adrenoceptor desensitization in vivo; salmeterol; down-regulation of Gsα
6.  Albuterol-induced downregulation of Gsα accounts for pulmonary β2-adrenoceptor desensitization in vivo 
Journal of Clinical Investigation  2000;106(1):125-135.
The aim of the present study was to develop a chronic in vivo model of pulmonary β2-adrenoceptor desensitization and to elucidate the nature and molecular basis of this state. Subcutaneous infusion of rats with albuterol for 7 days compromised the ability of albuterol, given acutely, to protect against acetylcholine-induced bronchoconstriction. The bronchoprotective effect of prostaglandin E2, but not forskolin, was also impaired, indicating that the desensitization was heterologous and that the primary defect in signaling was upstream of adenylyl cyclase. β2-Adrenoceptor density was reduced in lung membranes harvested from albuterol-treated animals, and this was associated with impaired albuterol-induced cyclic adenosine monophosphate (cAMP) accumulation and activation of cAMP-dependent protein kinase ex vivo. Gsα expression was reduced in the lung and tracheae of albuterol-treated rats, and cholera toxin–induced cAMP accumulation was blunted. Chronic treatment of rats with albuterol also increased cAMP phosphodiesterase activity and G protein–coupled receptor kinase-2, but the extent to which these events contributed to β2-adrenoceptor desensitization was unclear given that forskolin was active in both groups of animals and that desensitization was heterologous. Collectively, these results indicate that albuterol effects heterologous desensitization of pulmonary Gs-coupled receptors in this model, with downregulation of Gsα representing a primary molecular etiology.
PMCID: PMC314356  PMID: 10880056

Results 1-6 (6)