Response to hypoxia of pulmonary arteries in chronic obstructive pulmonary disease: an<i>in vitro</i>study

Peinado, Víctor I.; Santos, Salud; Ramírez, Josep; Roca, Josep; Rodríguez-Roisin, Roberto; Barberà, Joan Albert

doi:10.1183/09031936.02.00282002

Cited by 36 publications

(25 citation statements)

References 28 publications

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“…Diseases exposing lungs to chronic hypoxia such as chronic obstructive pulmonary disease are known to both contribute to the development of pulmonary hypertension in humans (7) and to be associated with a loss of the HPV response, which maintains ventilation to perfusion ratios (25). The results of this study detected evidence that increased extracellular hydrogen peroxide could be a factor in how chronic hypoxia can promote an impairment of HPV under conditions where pulmonary hypertension develops.…”

Section: Perspectives and Significancesupporting

confidence: 49%

“…A loss of the hypoxic pulmonary vasoconstriction (HPV) response which maintains ventilation to perfusion ratios is seen in humans with chronic obstructive pulmonary disease (COPD) and in pulmonary arteries isolated from these individuals (25). Studies in animal models of chronic hypoxia have provided evidence for processes that are associated with increased generation of reactive oxygen species (ROS) from sources, including various Nox oxidases participating in the progression of hypoxia-induced pulmonary hypertension development (10,12,13,15,19,21,23).…”

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confidence: 99%

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Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

Patel

Alhawaj

Wolin

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Patel D, Alhawaj R, Wolin MS. Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide. Am J Physiol Regul Integr Comp Physiol 307: R426 -R433, 2014. First published June 15, 2014 doi:10.1152/ajpregu.00257.2013.-Exposing mice to a chronic hypoxic treatment (10% oxygen, 21 days) that promotes pulmonary hypertension was observed to attenuate the pulmonary vasoconstriction response to acute hypoxia (HPV) both in vivo and in isolated pulmonary arteries. Since catalase restored the HPV response in isolated arteries, it appeared to be attenuated by extracellular hydrogen peroxide. Chronic hypoxia promoted the detection of elevated lung superoxide, extracellular peroxide, extracellular SOD expression, and protein kinase G (PKG) activation [based on PKG dimerization and vasodilator-stimulated phosphoprotein (VASP) phosphorylation], suggesting increased generation of extracellular peroxide and PKG activation may contribute to the suppression of HPV. Aorta from mice exposed to 21 days of hypoxia also showed evidence for extracellular hydrogen peroxide, suppressing the relaxation response to acute hypoxia. Peroxide appeared to partially suppress contractions to phenylephrine used in the study of in vitro hypoxic responses. Treatment of mice with the heme precursor ␦-aminolevulinic acid (ALA; 50 mg·kg Ϫ1 ·day Ϫ1 ) during exposure to chronic hypoxia was examined as a pulmonary hypertension therapy because it could potentially activate beneficial cGMP-mediated effects through promoting a prolonged protoporphyrin IX (PpIX)-elicited activation of soluble guanylate cyclase. ALA attenuated pulmonary hypertension, increases in both superoxide and peroxide, and the suppression of in vitro and in vivo HPV responses. ALA generated prolonged detectible increases in PpIX and PKG-associated phosphorylation of VASP, suggesting PKG activation may contribute to suppression of pulmonary hypertension and prevention of alterations in extracellular peroxide that appear to be attenuating HPV responses caused by chronic hypoxia. aminolevulinic acid; hypoxic pulmonary vasoconstriction; protein kinase G; pulmonary hypertension CHRONIC HYPOXIA IS KNOWN to contribute to the development of pulmonary hypertension in humans with chronic obstructive pulmonary disease (7), and intermittent hypoxia associated with sleep apnea promotes both pulmonary and systemic hypertension (9). A loss of the hypoxic pulmonary vasoconstriction (HPV) response which maintains ventilation to perfusion ratios is seen in humans with chronic obstructive pulmonary disease (COPD) and in pulmonary arteries isolated from these individuals (25). Studies in animal models of chronic hypoxia have provided evidence for processes that are associated with increased generation of reactive oxygen species (ROS) from sources, including various Nox oxidases participating in the progression of hypoxia-induced pulmonary hypertension development (10, 12, 13, 15, 19, 21, 23). Previous studies in pulm...

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Section: Perspectives and Significancesupporting

confidence: 49%

mentioning

confidence: 99%

Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

Patel

Alhawaj

Wolin

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Indeed, hypoxic pulmonary vasoconstriction is less active in patients with severe structural impairment of pulmonary muscular arteries [14]. Furthermore, in isolated pulmonary artery rings, it has been recently shown that the magnitude of contraction induced by hypoxic stimulus is inversely related to the endothelial function and directly related to the arterial PO 2 [41]. These findings suggest that the impairment of endothelial function is associated with an altered response to hypoxic stimulus that further worsens gas exchange.…”

Section: Hypoxic Pulmonary Vasoconstrictionmentioning

confidence: 73%

“…At this stage, the reactivity of pulmonary arteries to hypoxia might also be altered in some patients with mild COPD [16,34,41], hence contributing to alveolar ventilation/perfusion ratio (V9A/Q9) mismatching and promoting the development of arterial hypoxaemia. In this scenario, sustained exposure to hypoxaemia may induce further pulmonary vascular remodelling thus amplifying the initial effects of cigarette-smoke products ( fig.…”

Section: Mechanisms Of Pulmonary Vascular Changesmentioning

confidence: 99%

Pulmonary hypertension in chronic obstructive pulmonary disease

Barberà

Peinado²,

Santos³

2003

Eur Respir J

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Pulmonary hypertension in chronic obstructive pulmonary disease. J.A. Barberà, V.I. Peinado, S. Santos. #ERS Journals Ltd 2003. ABSTRACT: Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). Its presence is associated with shorter survival and worse clinical evolution. In COPD, pulmonary hypertension tends to be of moderate severity and progresses slowly. However, transitory increases of pulmonary artery pressure may occur during exacerbations, exercise and sleep. Right ventricular function is only mildly impaired with preservation of the cardiac output.Structural and functional changes of pulmonary circulation are apparent at the initial stages of COPD. Recent investigations have shown endothelial dysfunction and changes in the expression of endothelium-derived mediators that regulate vascular tone and cell growth in the pulmonary arteries of patients with mild disease. Some of these changes are also present in smokers with normal lung function. Accordingly, it has been postulated that the initial event in the natural history of pulmonary hypertension in COPD could be the lesion of pulmonary endothelium by cigarettesmoke products.Long-term oxygen administration is the only treatment that slows down the progression of pulmonary hypertension in chronic obstructive pulmonary disease. Nevertheless, with this treatment pulmonary artery pressure rarely returns to normal values and the structural abnormalities of pulmonary vessels remain unaltered. Vasodilators are not recommended on the basis of their minimal clinical efficacy and because they impair pulmonary gas exchange. Recognition of the role of endothelial dysfunction in the physiopathology of pulmonary hypertension in chronic obstructive pulmonary disease opens new perspectives for the treatment of this complication. Eur Respir J 2003; 21: 892-905.

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“…The group has focused its activity on the cellular and molecular mechanisms of pulmonary vascular abnormalities associated with COPD. The major achievements of the group have been as follows: 1) demonstration that changes in pulmonary arteries occur at early stages [2,3]; 2) characterisation of the cellular and molecular changes in pulmonary arteries [4]; 3) implication of cigarette smoking in the pathogenesis of pulmonary vascular abnormalities through an inflammatory mechanism [5]; 4) impact of endothelial dysfunction on the vascular response to hypoxia and gas exchange regulation [6]; 5) characterisation of mediators that contribute to vascular remodelling [7]; and 6) identification of vascular progenitor cells in the intima of pulmonary arteries from patients with COPD [1]. The group takes part in the European Union-funded Integrated Project PULMOTENSION.…”

Section: My Research As Part Of My Working Group/ Research Teammentioning

confidence: 99%

Plasticity of vascular progenitor cells: Implications in pulmonary vascular remodelling in COPD

Díez¹,

Peinado²,

Ferrer³

et al. 2006

European Respiratory Review

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WINNING ABSTRACT: Vascular progenitor cells (VPC) have shown in vitro and in vivo their ability to differentiate into endothelial cells (EC). Some evidence suggests that the plasticity of these cells to differentiate into other cell types might contribute not only to angiogenesis but also to perpetuate vascular lesions. Studies done in pulmonary arteries (PA) of patients with COPD have demonstrated the presence of VPC infiltrating the intima. Since intimal thickening is mainly constituted by smooth muscle cells (SMC), we asked whether VPC could play a role in wall thickening. Accordingly, the objective was to evaluate in vitro the plasticity of VPC to differentiate into SMC and EC of human PA. G-CSF-mobilized peripheral blood CD133+ cells from a commercial primary line were expanded and labelled with acetylated-LDL-DiI for tracking cell purposes. Then, cells were co-cultured with commercial primary lines of human PA EC or SMC (n53). As control, CD133+ cells were cultured alone, with minimal medium with or without VEGF (50ng?ml -1 ). After 6 and 12 days of growth, the phenotype of cultures was characterized by immunofluorescence with: lectin, a-actin and CD31. Cells were also evaluated morphologically. After 6 days, VPC acquired the morphology and the phenotype of the cells with which they were co-cultured, EC (lectin+, CD31+, a-actin-) or SMC (a-actin+, lectin-, CD31-). VPC cultured 12 days alone or with VEGF did not acquire typical morphology and markers of mature EC or SMC of PA. We conclude that VPC have the potential to differentiate in vitro into SMC, and that this plasticity could contribute to perpetuate pulmonary vascular remodelling in COPD.

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Response to hypoxia of pulmonary arteries in chronic obstructive pulmonary disease: anin vitrostudy

Cited by 36 publications

References 28 publications

Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide

Pulmonary hypertension in chronic obstructive pulmonary disease

Plasticity of vascular progenitor cells: Implications in pulmonary vascular remodelling in COPD

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