Polyphenol-Rich Blackcurrant Juice Prevents Endothelial Dysfunction in the Mesenteric Artery of Cirrhotic Rats with Portal Hypertension: Role of Oxidative Stress and the Angiotensin System.

Chronic liver diseases with portal hypertension are characterized by a progressive vasodilatation, endothelial dysfunction, and NADPH oxidase-derived vascular oxidative stress, which have been suggested to involve the angiotensin system. This study evaluated the possibility that oral intake of polyphenol-rich blackcurrant juice (PRBJ), a rich natural source of antioxidants, prevents endothelial dysfunction in a rat model of cirrhosis induced by chronic bile duct ligation (CBDL), and, if so, determined the underlying mechanism. Male Wistar rats received either control drinking water or water containing 60 mg/kg gallic acid equivalents of PRBJ for 3 weeks before undergoing surgery with CBDL or sham surgery. After 4 weeks, vascular reactivity was assessed in mesenteric artery rings using organ chambers. Both the acetylcholine-induced nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations in mesenteric artery rings were significantly reduced in CBDL rats compared to sham rats. An increased level of oxidative stress and expression of NADPH oxidase subunits, COX-2, NOS, and of the vascular angiotensin system are observed in arterial sections in the CBDL group. Chronic intake of PRBJ prevented the CBDL-induced impaired EDH-mediated relaxation, oxidative stress, and expression of the different target proteins in the arterial wall. In addition, PRBJ prevented the CBDL-induced increase in the plasma level of proinflammatory cytokines (interleukin [IL]-1α, monocyte chemotactic protein 1, and tumor necrosis factor α) and the decrease of the anti-inflammatory cytokine, IL-4. Altogether, these observations indicate that regular ingestion of PRBJ prevents the CBDL-induced endothelial dysfunction in the mesenteric artery most likely by normalizing the level of vascular oxidative stress and the angiotensin system.

Effect of the oestrogen receptor antagonist fulvestrant on the cirrhotic rat lung.

It has been postulated that cirrhosis-related lung vasodilatation and the subsequent hepatopulmonary syndrome are partly explained by an increased estradiol level through an enhanced endothelial formation of nitric oxide (NO). In this study, we assessed whether the oestrogen receptor antagonist fulvestrant (F) improves cirrhosis-related lung abnormalities. Cirrhosis was induced in rats by chronic bile duct ligation (CBDL). Four groups were studied: CBDL, CBDL+F, sham, and sham+F. Histological, immunohistochemical, and Western blot analyses were performed on lung samples. In the lung, the endothelial NO synthase and the nitrotyrosine protein expressions were increased in CBDL as compared to sham rats. Both parameters were significantly reduced by fulvestrant in the CBDL rats. Surprisingly, the level of pVASP (an indirect marker of NO formation and action) was decreased in CBDL rats, and fulvestrant had no effect on this parameter. The level of the vascular endothelial growth factor, the diameter of small lung vessels, and the number of macrophages were increased in CBDL lungs in comparison with sham lungs, and these parameters were unaffected by fulvestrant treatment. In conclusion, fulvestrant may not be relevant to improve lung abnormalities in cirrhosis because NO may not be biologically active and because key events contributing to the lung abnormalities are not affected by fulvestrant.

Probiotics (VSL#3) prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.

AIMS: Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated. METHODS: Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS: Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels. CONCLUSIONS: These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.

Impact of 3D conformal radiotherapy on lung function of patients with lung cancer: a prospective study.

BACKGROUND: The development of three-dimensional conformal radiotherapy (3D-RT) has enabled the restriction of the dose to normal lung, limiting radiation-induced lung injury. OBJECTIVES: This study was designed to describe the time course of lung function until 7.5 months after 3D-RT in patients with lung cancer, and assess the relationship between lung function changes and dose-volume histogram (DVH) analysis or computed tomography scan changes. Radiation doses were optimized according to recent guidelines. METHODS: Sixty-five lung cancer patients treated with 3D-RT agreed to participate in this prospective, hospital-based study. Lung volumes, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) were measured before radiotherapy (RT), 10 weeks, 4 and 7.5 months after the beginning of 3D-RT. RESULTS: Eleven lung cancer patients (17%) developed grade 2-3 respiratory symptoms after RT. At 7.5 months, vital capacity (VC) was 96 ± 2%, total lung capacity (TLC) 95 ± 2%, FEV1 93 ± 2% and DLCO 90 ± 2% of the initial value. Only 15% of patients showed pulmonary function reduction > 20%. Patients with FEV1 or DLCO < 60% before RT did not show significant changes after RT. There were weak correlations between reduction of VC, TLC, FEV1 or DLCO and radiation dosimetric parameters and between reduction of VC or FEV1 and radiation-induced pneumonitis images. CONCLUSIONS: In lung cancer, the reduction of lung function within 7.5 months after 3D-RT was small and correlated, albeit weakly, with DVH parameters. Patients with initially impaired lung function showed tiny changes in spirometry and DLCO values.

Asthma as a cause of persistent dyspnea in treated myasthenia gravis patients.

AIMS: The aim of this study was to evaluate the proportion of patients with treated myasthenia gravis (MG) who present with dyspnea not related to MG. METHODS: We analyzed the files of 63 consecutive adult patients with treated MG and persistent dyspnea who had been referred to our Pulmonary Function Test (PFT) Department between 2000 and 2010. RESULTS: We observed that asthma was the first cause of MG-unrelated dyspnea in MG patients, with 9 patients (14%) presenting with asthma-related PFT abnormalities. Six patients had asthma for several years before developing MG, and 3 patients (4%) developed asthma a few months after MG was diagnosed, suggesting a non-coincidental association between the two conditions. In all 3 cases, asthma appeared in elderly patients with severe late-onset AchR-Ab- positive MG, treated with pyridostigmine and corticosteroids and/or intravenous immunoglobulins. In all 3 patients, ß(2)-adrenergic agonist treatment allowed only partial control of dyspnea. In one case, respiratory symptoms were alleviated when pyridostigmine dosage was reduced. CONCLUSIONS: Patients with treated MG and persistent dyspnea should be investigated for asthma using PFT before being diagnosed with refractory MG. If asthma is diagnosed, a bronchodilator treatment should be instituted and a reduction in pyridostigmine dosage should be proposed.

Can exhaled NO fraction predict radiotherapy-induced lung toxicity in lung cancer patients?

BACKGROUND: A large increase in nitric oxide fraction (FeNO) after radiotherapy (RT) for lung cancer may predict RT-induced lung toxicity. METHODS: In this study, we assessed the relationships between FeNO variations and respiratory symptoms, CT scan changes or dose volume histogram (DVH) parameters after RT. We measured FeNO before RT, 4, 5, 6, 10 weeks, 4 and 7.5 months after RT in 65 lung cancer patients. RESULTS: Eleven lung cancer patients (17%) complained of significant respiratory symptoms and 21 (31%) had radiation pneumonitis images in > 1/3 of the irradiated lung after RT. Thirteen patients (20%) showed increases in FeNO > 10 ppb. The sensitivity and specificity of a > 10 ppb FeNO increase for the diagnosis of RT-associated respiratory symptoms were 18% and 83%, respectively. There was no correlation between DVH parameters or CT scan changes after RT and FeNO variations. Three patients (5%) showed intriguingly strong (2 or 3-fold, up to 55 ppb) and sustained increases in FeNO at 4 and 5 weeks, followed by significant respiratory symptoms and/or radiation-pneumonitis images. CONCLUSION: Serial FeNO measurements during RT had a low ability to identify lung cancer patients who developed symptoms or images of radiation pneumonitis. However, three patients presented with a particular pattern which deserves to be investigated.

Impact of altered alveolar volume on the diffusing capacity of the lung for carbon monoxide in obesity.

BACKGROUND: Studies on the diffusing capacity of the lung for carbon monoxide (DL(CO)) in obese patients are conflicting, some studies showing increased DL(CO) and others unaltered or reduced values in these subjects. OBJECTIVES: To compare obese patients to controls, examine the contribution of alveolar volume (VA) and CO transfer coefficient (K(CO)) to DL(CO), and calculate DL(CO) values adjusted for VA. METHODS: We measured body mass index (BMI), waist circumference (WC), spirometry and DL(CO) in 98 adult obese patients without cardiopulmonary or smoking history and 48 healthy subjects. All tests were performed in the same laboratory. RESULTS: Using conventional reference values, mean DL(CO) and VA were lower (-6%, p < 0.05, and -13%, p < 0.001, respectively), and K(CO) was higher (+9%, p < 0.05) in obese patients than in controls. VA decreased whereas K(CO) increased with increasing BMI and WC in the obese group. Patients with lower DL(CO) had low K(CO) in addition to decreased VA. In contrast, some obese patients maintained normal VA, which, coupled with high K(CO), resulted in higher DL(CO). The main result is that diffusion capacity differences between obese patients and controls disappeared using reference equations adjusting DL(CO) for VA. CONCLUSIONS: Using conventional reference equations, our obese patients show slightly lower mean DL(CO,) lower mean VA and higher mean K(CO) than controls, but with a large range of DL(CO) values and patterns. Adjusting DL(CO) for VA suggests that low lung volumes are the main cause of low DL(CO) and high K(CO) values in obese patients.

The opening interrupter technique for respiratory resistance measurements in children.

BACKGROUND AND OBJECTIVE: The interrupter resistance (Rint) can be calculated from various estimates of alveolar pressure based on mouth pressure during occlusion. We compared Rint, as measured by the opening interrupter technique (Rint1), and the linear back-extrapolation method (Rint2), with the 'gold standard' airway resistance measured by plethysmography (Raw). METHODS: The study included 32 asthmatic children and 11 children with cystic fibrosis, aged 5 to 18 years, who were categorized into non-obstructed (NObs) (n = 27) and obstructed (Obs) (n = 16) groups. Spirometry and the three different resistance measurements were performed on all children. Rint1 and Raw were assessed after a bronchodilator (BD) test in 16 and nine children, respectively, in the Obs group. RESULTS: Raw (0.48 ± 0.20 kPa.s/L) was lower than Rint1 (1.04 ± 0.34 kPa.s/L) and Rint2 (0.63 ± 0.18 kPa.s/L) (P < 0.001). Raw, but neither Rint1 nor Rint2, was significantly higher in the Obs group than in the NObs group (0.57 ± 0.23 vs 0.42 ± 0.16 kPa.s/L, P < 0.05). The differences Rint1-Raw and Rint2-Raw were correlated with FEV(1) /VC (P < 0.01 and P < 0.001), and Rint1-Raw was correlated with height (P < 0.001). After BD significant changes in Rint1 and Raw were observed in 5/9 and 7/9 children, respectively. CONCLUSIONS: Rint2, as well as Rint1, may be underestimated in the most Obs children and may therefore fail to detect severe obstruction. Rint1 is likely to include a non-negligible contribution from the tissue component, especially in the youngest children. Although not different between Obs and NObs children at baseline, Rint1 did detect bronchodilation in some Obs children.

Losartan prevents portal hypertension-induced, redox-mediated endothelial dysfunction in the mesenteric artery in rats.

BACKGROUND & AIMS: Advanced stages of portal hypertension are characterized by generalized vasodilatation and a hyperdynamic syndrome that leads to complications such as hepatopulmonary syndrome. We assessed the endothelial function--particularly the formation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)--in rats following common bile duct ligation (CBDL) to determine the underlying mechanisms of these processes. METHODS: Reactivity of mesenteric artery rings from male Wistar rats was determined in organ chambers. The expression levels of connexins (Cx) (Cx37, Cx40, Cx43), intermediate and small conductance Ca(2+)-activated K(+) channels (IK(Ca), SK(Ca)), endothelial NO synthase (eNOS), NADPH oxidase subunits, and nitrotyrosines were assessed by immunohistochemistry in mesenteric and pulmonary arteries. The vascular formation of reactive oxygen species (ROS) was evaluated using dihydroethidine. Control rats or those that had undergone CBDL were given either the NADPH oxidase inhibitor apocynin or the angiotensin II receptor type 1 antagonist losartan. RESULTS: Decreased EDHF-mediated relaxations to acetylcholine and red wine polyphenols were observed in CBDL rats, compared with controls, whereas the level of NO-mediated relaxation was similar. Impaired EDHF-mediated relaxations were associated with reduced vascular expression of Cx37, Cx40, Cx43, IK(Ca) and SK(Ca); increased expression of eNOS and NADPH oxidase subunits; and increased vascular formation of ROS and peroxynitrites. These effects were prevented by exposure to apocynin or losartan. CONCLUSIONS: CBDL is associated with reduced EDHF-mediated relaxations in the mesenteric artery, whereas NO-mediated relaxations persisted. These findings indicate that impaired EDHF-mediated relaxation involves an excessive vascular oxidative stress, most likely following activation of angiotensin II type 1 receptors.

Lung function after lobectomy: a randomized, double-blinded trial comparing thoracic epidural ropivacaine/sufentanil and intravenous morphine for patient-controlled analgesia.

BACKGROUND: Although thoracic epidural analgesia (TEA) is considered superior to IV opioids for postoperative analgesia after thoracic surgery, a few studies clearly demonstrate an improvement in pulmonary function attributable to TEA using a local anesthetic in combination with an opioid. METHODS: In this prospective, randomized, double-blind study, we compared the effects of TEA with ropivacaine and sufentanil (TEA group) to IV morphine (IV group), as they affected pain and pulmonary function after lobectomy in 68 patients. Pain intensity, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, forced expiratory flows, and sniff nasal inspiratory pressure as a marker of inspiratory muscle strength were measured from the first to the fourth postoperative day. RESULTS: Pain relief was better in the TEA group at rest and on coughing (P < 0.001). The impairment of FVC and FEV1 was less in the TEA group when compared with that in the IV group (P < 0.001 and P = 0.003, respectively). Sniff nasal inspiratory pressure, FEV1/FVC ratio, and expiratory flow values decreased similarly in both groups. In-hospital mortality, as well as postoperative pulmonary complications, was not different between groups. CONCLUSION: After lobectomy, TEA enables a significant increase in pulmonary function concomitant with better pain relief than systemic morphine, although a modest intercostal motor block may occur.