Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM

Manral, Sushma; Bhatia, Sumati; Sinha, Rajesh; Kumar, Ajit; Rohil, Vishwajeet; Arya, Amit; Dhawan, Ashish; Arya, Pragya; Joshi, Rekha; Sreedhara, Sreerama C.; Gangopadhyay, Sukanya; Bansal, Surendra K.; Chatterjee, Suvro; Chaudhury, N. K.; Vijayan, V K; Saso, Luciano; Parmar, Virinder S.; DePass, Anthony L.; Prasad, Ashok K.; Raj, Hanumantharao G.

doi:10.1016/j.biochi.2011.04.004

Cited by 7 publications

(6 citation statements)

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“…We cannot exclude that the increased serum nitrite concentration might be related to increased iNOS activity of circulating and vascular cells in COPD and that the altered concentration of serum ADMA and SDMA might also modulate iNOS function on these cells. Blood lymphocytes showed increased iNOS activity in COPD [42], however, neutrophil granulocytes, present in elevated number in patients, did not show iNOS activity in healthy humans [43] with no data available in patients with COPD. In addition, pulmonary arteries showed decreased eNOS, but increased iNOS expression in patients with end-stage disease [44], but it was not confirmed by another study [45].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD

et al. 2019

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Background Chronic obstructive pulmonary disease (COPD) is related to endothelial dysfunction and the impaired generation of nitric oxide (NO) from L-arginine by the endothelial NO synthase (eNOS). The relationship between eNOS dysfunctionality and airway inflammation is unknown. We assessed serum asymmetric and symmetric dimethylarginine (ADMA and SDMA) and nitrite/nitrate concentrations, indicators of eNOS function, in patients with COPD and correlated them with markers of inflammation. Methods We recruited 15 control smokers, 29 patients with stable and 32 patients with exacerbated COPD requiring hospitalization (20 of them were measured both at admission and discharge). Serum L-arginine, ADMA, SDMA, nitrite and nitrate were measured and correlated with airway inflammatory markers (fractional exhaled nitric oxide concentration - F ENO, sputum nitrite and nitrate, sputum cellularity), serum C-reactive protein - CRP, white blood cell count, lung function and blood gases. ANOVA, t-tests and Pearson correlation were used (mean ± SD or geometric mean ± geometric SD for nitrite/nitrate). Results Serum L-arginine/ADMA, a marker of substrate availability for eNOS, was lower in stable (214 ± 58, p < 0.01) and exacerbated COPD (231 ± 68, p < 0.05) than in controls (287 ± 64). The serum concentration of SDMA, a competitor of L-arginine transport, was elevated during an exacerbation (0.78 ± 0.39 μM) compared to stable patients (0.53 ± 0.14 μM, p < 0.01) and controls (0.45 ± 0.14 μM, p < 0.001). ADMA correlated with blood neutrophil percentage ( r = 0.36, p < 0.01), F ENO ( r = 0.42, p < 0.01) and a tendency for positive association was observed to sputum neutrophil count ( r = 0.33, p = 0.07). SDMA correlated with total sputum inflammatory cell count ( r = 0.61, p < 0.01) and sputum neutrophil count ( r = 0.62, p < 0.01). Markers were not related to lung function, blood gases or CRP. L-arginine/ADMA was unchanged, but serum SDMA level decreased (0.57 ± 0.42 μM, p < 0.05) after systemic steroid treatment of the exacerbation. Serum nitrite level increased in stable and exacerbated disease (4.11 ± 2.12 and 4.03 ± 1.77 vs. control: 1.61 ± 1.84 μM, both p < 0.001). Conclusions Our data suggest impaired eNOS function in stable COPD, which is transiently aggravated during an exacerbation and partly reversed by systemic steroid treatment. Serum ADMA and SDMA correlate with airway inflammatory markers implying a possible effect of anti-inflammatory th...

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Section: Discussionmentioning

confidence: 99%

Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD

et al. 2019

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“…The pathophysiology of COPD is a multifactorial process with an complex inflammatory cell profile including eosinophils [7], macrophages [8], neutrophils [9], and lymphocytes [10]. The levels of some cytokines, such as interleukin(IL)-8 [11], interleukin(IL)-6 [12], tumor necrosis factor alpha (TNF-A) [13], and vascular endothelial growth factor (VEGF) [14] are increased in stable COPD patients, suggesting their key-roles in the pathogenesis of COPD.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in ADAM33 are associated with airway inflammation and lung function in COPD

et al. 2014

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BackgroundGenetic factors play a role in the development and severity of chronic obstructive pulmonary disease (COPD). The pathogenesis of COPD is a multifactorial process including an inflammatory cell profile. Recent studies revealed that single nucleotide polymorphisms (SNPs) within ADAM33 increased the susceptibility to COPD through changing the airway inflammatory process and lung function.MethodsIn this paper, we investigated associations of four polymorphisms (T1, T2, S2 and Q-1) of ADAM33 as well as their haplotypes with pulmonary function and airway inflammatory process in an East Asian population of patients with COPD.ResultsWe found that T1, T2 and Q-1 were significantly associated with the changes of pulmonary function and components of cells in sputum of COPD, and T1 and Q-1 were significantly associated with cytokines and mediators of inflammation in airway of COPD in recessive models. 10 haplotypes were significantly associated with transfer factor of the lung for carbon monoxide in the disease state, 4 haplotypes were significantly associated with forced expiratory volume in one second, and other haplotypes were associated with airway inflammation.ConclusionsWe confirmed for the first time that ADAM33 was involved in the pathogenesis of COPD by affecting airway inflammation and immune response in an East Asian population. Our results made the genetic background of COPD, a common and disabling disease, more apparent, which would supply genetic support for the study of the mechanism, classification and treatment for this disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2466-14-173) contains supplementary material, which is available to authorized users.

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“…Intracellular Ca 2+ was reported to regulate MUC2 expression [ 34 , 35 ] and mucin secretion from airway goblet cells [ 36 ]. In addition, a study demonstrated increased intracellular Ca 2+ levels in lymphocytes of COPD patients, which correlated positively with the spirometric grade of COPD [ 37 ]. Gene expression microarray analysis of human bronchial epithelial cells identified overexpression of EFCAB4A during mucociliary differentiation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease

Investigators

2014

Respir Res

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BackgroundChronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.MethodsWe analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.ResultsFor CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P = 4.99 × 10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P = 4.99 × 10-7).ConclusionsWe found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.Trial registrationClinicalTrials.gov NCT00608764, NCT00292552Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0113-2) contains supplementary material, which is available to authorized users.

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Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM

Cited by 7 publications

References 74 publications

Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD

Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD

Genetic variants in ADAM33 are associated with airway inflammation and lung function in COPD

Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease

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