Victor I. Peinado

Pulmonary hypertension in chronic obstructive pulmonary disease

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 cigarette-smoke 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.

Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD

Intimal enlargement of pulmonary arteries is an early change in chronic obstructive pulmonary disease (COPD). The cellular and extracellular components that are involved in this enlargement are unknown. The present study was designed to characterize the structural changes occurring in pulmonary muscular arteries in the initial disease stages. Lung specimens from patients with moderate COPD (n=8; forced expiratory volume in one second (FEV1), 66±10% predicted) and smokers without airflow obstruction (n=7; FEV1, 86±6% pred), were investigated by histochemistry to characterize extracellular matrix proteins and by immunohistochemistry to identify intrinsic cells of the vascular wall. In both COPD patients and smokers, the majority of cells present in the enlarged intimas were stained by specific smooth muscle cell (SMC) markers. No staining with endothelial or fibroblast markers was shown. A proportion of SMCs did not stain with desmin, suggesting cellular heterogeneity in this population. Elastin was the most abundant extracellular matrix protein and collagen was seen in a lower proportion. The amount of collagen was related to the intimal thickness (p<0.001). The findings demonstrated smooth muscle cell proliferation, as well as elastin and collagen deposition, in the thickened intimas of pulmonary arteries in moderate chronic obstructive pulmonary disease patients and smokers, suggesting that these abnormalities may originate at an early stage in cigarette smoke-induced respiratory disease.

Endothelial dysfunction in pulmonary arteries of patients with mild COPD

To investigate whether endothelial dysfunction of pulmonary arteries (PA) is present in patients with mild chronic obstructive pulmonary disease (COPD) and to what extent it is related to the morphological abnormalities of PA, we studied 41 patients who underwent lung resection. Patients were divided into the following groups: nonsmokers ( n = 7), smokers with normal lung function ( n = 13), and COPD ( n = 21). Endothelium-dependent relaxation mediated by nitric oxide was evaluated in vitro in PA rings exposed to cumulative concentrations of acetylcholine (ACh) and ADP. Structural abnormalities of PA were assessed morphometrically. PA of COPD patients developed lower maximal relaxation in response to ADP than both nonsmokers and smokers ( P < 0.05 each) and a trend to reduced relaxation in response to ACh ( P = 0.08). Maximal relaxation to ADP correlated with the degree of airflow obstruction ( r = 0.48, P < 0.01). Morphometrical analysis of PA revealed thicker intimas, especially in small arteries, in both smokers and COPD compared with nonsmokers ( P < 0.05 each). We conclude that endothelial dysfunction of PA is already present in patients with mild COPD. In these patients, as well as in smokers with normal lung function, small arteries show thickened intimas, suggesting that tobacco consumption may play a critical role in the pathogenesis of pulmonary vascular abnormalities in COPD.To investigate whether endothelial dysfunction of pulmonary arteries (PA) is present in patients with mild chronic obstructive pulmonary disease (COPD) and to what extent it is related to the morphological abnormalities of PA, we studied 41 patients who underwent lung resection. Patients were divided into the following groups: nonsmokers (n = 7), smokers with normal lung function (n = 13), and COPD (n = 21). Endothelium-dependent relaxation mediated by nitric oxide was evaluated in vitro in PA rings exposed to cumulative concentrations of acetylcholine (ACh) and ADP. Structural abnormalities of PA were assessed morphometrically. PA of COPD patients developed lower maximal relaxation in response to ADP than both nonsmokers and smokers (P < 0.05 each) and a trend to reduced relaxation in response to ACh (P = 0.08). Maximal relaxation to ADP correlated with the degree of airflow obstruction (r = 0.48, P < 0. 01). Morphometrical analysis of PA revealed thicker intimas, especially in small arteries, in both smokers and COPD compared with nonsmokers (P < 0.05 each). We conclude that endothelial dysfunction of PA is already present in patients with mild COPD. In these patients, as well as in smokers with normal lung function, small arteries show thickened intimas, suggesting that tobacco consumption may play a critical role in the pathogenesis of pulmonary vascular abnormalities in COPD.

Pulmonary Vascular Involvement in COPD

Alterations in pulmonary vessel structure and function are highly prevalent in patients with COPD. Vascular abnormalities impair gas exchange and may result in pulmonary hypertension, which is one of the principal factors associated with reduced survival in COPD patients. Changes in pulmonary circulation have been identified at initial disease stages, providing new insight into their pathogenesis. Endothelial cell damage and dysfunction produced by the effects of cigarette smoke products or inflammatory elements is now considered to be the primary alteration that initiates the sequence of events resulting in pulmonary hypertension. Cellular and molecular mechanisms involved in this process are being extensively investigated. Progress in the understanding of the pathobiology of pulmonary hypertension associated with COPD may provide the basis for a new therapeutic approach addressed to correct the imbalance between endothelium-derived vasoactive agents. The safety and efficacy of endothelium-targeted therapy in COPD-associated pulmonary hypertension warrants further investigation in randomized clinical trials.

Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats

The prevalence of cigarette smoking (CS) is increased among obese subjects, who are susceptible to develop nonalcoholic fatty liver disease (NAFLD). We investigated the hepatic effects of CS in control and obese rats. Control and obese Zucker rats were divided into smokers and nonsmokers (n = 12 per group). Smoker rats were exposed to 2 cigarettes/day, 5 days/week for 4 weeks. The effects of CS were assessed by biochemical analysis, hepatic histological examination, immunohistochemistry, and gene expression analysis. Phosphorylation of AKT and extracellular signal‐regulated kinase (ERK) and quantification of carbonylated proteins were assessed by western blotting. As expected, obese rats showed hypercholesterolemia, insulin resistance, and histological features of NAFLD. Smoking did not modify the lipidic or glucidic serum profiles. Smoking increased alanine aminotransferase serum levels and the degree of liver injury in obese rats, whereas it only induced minor changes in control rats. Importantly, CS increased the histological severity of NAFLD in obese rats. We also explored the potential mechanisms involved in the deleterious effects of CS. Smoking increased the degree of oxidative stress and hepatocellular apoptosis in obese rats, but not in controls. Similarly, smoking increased the hepatic expression of tissue inhibitor of metalloproteinase‐1 and procollagen‐alpha2(I) in obese rats, but not in controls. Finally, smoking regulated ERK and AKT phosphorylation. The deleterious effects of CS were not observed after a short exposure (5 days). Conclusion: CS causes oxidative stress and worsens the severity of NAFLD in obese rats. Further studies should assess whether this finding also occurs in patients with obesity and NAFLD. (HEPATOLOGY 2010.)

Hematologic and Plasma Chemistry Values in Captive Psittacine Birds

Reference values for some hematologic parameters in 19 species and plasma chemical values in 11 species of Psittacine birds, including cockatoos, parrots, amazons, macaws, conures, and lories, were established for use in veterinary medicine. The following parameters were studied: hematocrit, hemoglobin concentration, erythrocyte number, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, erythrocyte dimensions, leukocyte number and differential leukocyte count, glucose, urea, uric acid, cholesterol, triglycerides, creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine phosphokinase, lactic dehydrogenase, gamma glutamyl transpeptidase, total plasma protein, albumin, globulins, albumin-globulin ratio, sodium, potassium, calcium, magnesium, total phosphorus, chloride, and osmolality. Hematologically, the Psittacine is a very homogeneous avian group, with small differences between species. They are, however, different from other groups of birds.

Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema.

RATIONALE Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available. OBJECTIVES To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions. METHODS Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done. MEASUREMENTS AND MAIN RESULTS The functionally essential sGC β1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils. CONCLUSIONS The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.

Response to hypoxia of pulmonary arteries in chronic obstructive pulmonary disease: an in vitro study

Patients with chronic obstructive pulmonary disease (COPD) show impaired hypoxic pulmonary vasoconstriction that might contribute to abnormal gas exchange and could be related to endothelial dysfunction in pulmonary arteries. The aim of the study was to investigate the response of PA to hypoxic stimulus in vitro in COPD, and the role of endothelium-derived nitric oxide (NO) in this response. The pulmonary arteries of 25 patients who underwent lung resection were studied. Patients were divided into controls, COPD+normoxaemia (COPDN) and COPD+hypoxaemia (COPDH). Hypoxic vasoconstriction (HV) was evaluated before and after stimulation or inhibition of the endothelial release of NO, and in the presence of exogenous NO. Compared with the other groups, HV was reduced in COPDH. The magnitude of HV correlated with the oxygen tension in arterial blood. The hypoxic stimulus induced greater contraction after stimulating endothelial release of NO, whereas its inhibition practically abolished HV. Exogenous NO completely inhibited HV. Maximal relaxation induced by endothelium-dependent vasodilators correlated with the magnitude of HV. In conclusion, pulmonary arteries of patients with chronic obstructive pulmonary disease and hypoxaemia have an impaired response to hypoxic stimulus, and the endothelial release of nitric oxide modulates hypoxic vasoconstriction. The depressed response of pulmonary arteries to hypoxia may contribute to abnormal gas exchange in chronic obstructive pulmonary disease.

Seasonal changes in hematology and blood chemistry of the freshwater turtle Mauremys caspica leprosa

Abstract 1. 1. Hematological and some plasma chemistry values were studied in adult stripe-necked terrapins (Mauremys caspica leprosa) in summer and autumn. 2. 2. Differences were detected in hematocrit, red cell count and hemoglobin concentration. However, hematimetric indexes remain unchanged. 3. 3. The erythrocyte dimensions do not change but the nucleus size was significantly lower in autumn turtles. 4. 4. Plasma concentrations of glucose, calcium and magnesium were lower in summer, whereas inorganic phosphorus was higher. 5. 5. Slight variations were also observed in total plasma protein concentration and their fractional composition, and in plasma osmolarity.

Haematology and blood chemistry values for several flamingo species

Reference values for some haematological and plasma chemical values in four species of clinically normal adult flamingos were established for use in avian medicine. The following variables were studied in rosy, greater, Chilean and lesser flamingos: haematocrit, haemoglobin concentration, erythrocyte and leucocyte counts, haematimetric indices, erythrocyte dimensions, glucose, urea, uric acid, cholesterol, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, phosphokinase, lactic dehydrogenase, total phosphorus, chloride, total plasma protein, albumin, globulins, albumin-globulin ratio, sodium, potassium, calcium, magnesium and osmolality.