Inhaled nitric oxide in patients with pulmonary hypertension due to valvular heart disease and chronic lung disease

The objective of this study was to investigate the effects of inhaled nitric oxide (NO) on chronic pulmonary hypertension (PH). Thirty patients with valvular heart diseases (n=8, group A), chronic lung diseases (n=16, group B), primary PH or PH due to collagen disease (n=6, group C) were studied. NO was delivered for 20 min at concentration of 5, 10, and 20 ppm in spontaneous respiration. After inhalation, percentages of systolic pulmonary artery pressure (%SPAP) levels in group A were significantly decreased compared with those for pre-inhalation by 12%, 14%, and 14% at 5, 10 and 20 ppm, respectively (p<0.05). In group B, %SPAP also significantly decreased by 7, 10, and 14% at 5, 10, and 20 ppm, respectively (p<0.05). However, inhaled NO did not significantly affect %SPAP in group C (p=0.4). There was no significant difference in gas exchange in any of the groups. However, 4 out of 8 patients in group A and 10 out of 16 patients in group B showed decreased partial pressure of arterial oxygen in response to inhaled NO. This study demonstrated that inhaled NO is a selective pulmonary vasodilator in decreasing pulmonary artery pressure (PAP); however, the reaction was different in line with the background disease cause of PH. NO inhalation was most effective on patients with moderate PAP. Furthermore, higher concentrations of NO would be risky in some patients with chronic PH.     

Multi-center European evaluation of HIV testing on serum and saliva samples

Sulphur dioxide (SO2) is an air pollutant implicated in the initiation of asthmatic symptoms. Glutathione (GSH) has been proposed to play a role in detoxification of SO2 through the sulfitolysis of glutathione disulphide (GSSG) to S-sulphoglutathione (GSSO3-). Rats were exposed to concentrations of SO2 between 5 and 100 ppm for 5 hr a day between 7 and 28 days. Lung injury as assessed by bronchoalveolar lavage and tissue GSH status were evaluated. SO2 5 ppm failed to elicit any lung injury or inflammatory response but did deplete GSH pools in lung, liver, heart and kidney. Activities of gamma-glutamylcysteine synthetase (GCS), glutathione peroxidase (GPx), glutathione S-transferase (GST) and glutathione reductase (GRed) in lung were lowered relative to those in control animals. In liver, GRed activity was decreased. SO2 50 ppm exposure also failed to elicit injury or inflammation but did lower inflammatory cell numbers in the circulation. Rats exposed to 50 ppm SO2 maintained tissue GSH status, but activities of GCS, GPx, GRed and gamma-glutamyltranspeptidase in lung and hepatic GRed and GPx were significantly lower than in control rats. Unaltered GST activity in lung and liver was suggestive of an impairment of the sulfitolysis reaction in these animals, perhaps through lower substrate flux through the GPx reaction, as GSSO3- is a known inhibitor of GST in the rat. Rats exposed to 100 ppm SO2 exhibited evidence of inflammation (120-fold increase in neutrophil numbers recovered in lavage fluid) and like the 5 ppm exposed rats had lower tissue GSH concentrations and GSH-related enzyme activities in lung. We conclude that sulfitolysis of GSSG does occur in vivo during SO2 exposure and that SO2, even in the absence of pulmonary injury, is a potent glutathione depleting agent.     

Effects of ozone and airway inflammation on glutathione status and iron homeostasis in the lungs of horses

OBJECTIVE: To investigate the effects of ozone and airway inflammation on indices of oxidant injury in horses. ANIMALS: 5 clinically normal horses and 25 horses referred for poor performance. PROCEDURE: Blood, tracheal wash, and bronchoalveolar lavage fluid samples were collected before and after ozone exposure (n = 5) or from clinical cases (n = 25), and were analyzed for reduced glutathione (GSH), glutathione disulfide (GSSG), and free and total iron (Fe) values. A scoring system (0 to 5) was used to assess airway inflammation on the basis of clinical signs and cytologic analysis of the tracheal wash and bronchoalveolar lavage fluid samples. RESULTS: Ozone induced significant (P < 0.05) increases in GSH (195.4 +/- 68.5 microM), GSSG (19.4 +/- 6.4 microM), and free (25.5 +/- 16.1 microM) and total (93.1 +/- 13.4 microM) Fe values in the pulmonary epithelial lining fluid, compared with preozone samples (49.2 +/- 18.6, 2.4 +/- 1.2, 0.0, and 33.1 +/- 5.9 microM, respectively). The presence of airway inflammation (19/25) was associated with high GSSG and free and total Fe, but not GSH, values in epithelial lining fluid, compared with values for clinically normal horses (6/25). There were no differences in the systemic values of GSH, GSSG, and free and total Fe between any of the groups. A strong correlation (r = 0.84; P < 0.001) existed between inflammation score and the glutathione redox ratio (GSSG/[GSH + GSSG]) in the 25 horses admitted for clinical examination. CONCLUSIONS: Oxidant injury in the lung will induce changes in the glutathione status and Fe homeostasis that could affect pathogenesis of the disease. CLINICAL RELEVANCE: Measurement of indices of oxidant injury may be useful in the diagnosis of airway inflammation and the response to inhaled oxidants.     

Influence of inhaled nitric oxide and hyperoxia on Na,K-ATPase expression and lung edema in newborn piglets

This study was undertaken to examine the combined effect of nitric oxide (NO) and hyperoxia on lung edema and Na,K-ATPase expression. Newborn piglets were exposed to room air (FiO2 = 0.21), room air plus 50 ppm NO, hyperoxia (FiO2 >/= 0.96) or to hyperoxia plus 50 ppm NO for 4-5 days. Animals exposed to NO in room air experienced only a slight decrease in Na,K-ATPase alpha subunit protein level. Hyperoxia, in the absence of NO, induced both the mRNA and the protein level of Na,K-ATP-ase alpha subunit and significantly increased wet lung weight, extravascular lung water, and alveolar permeability. NO in hyperoxia decreased the hyperoxic-mediated induction of Na,K-ATPase alpha subunit mRNA and protein while wet lung weight, extravascular lung water, and alveolar permeability remained elevated. These results suggest that 50 ppm of inhaled NO may not improve hyperoxic-induced lung injury and may interfere with the expression of Na,K-ATPase which constitutes a part of the cellular defense mechanism against oxygen toxicity.     

Red blood cell glutathione and plasma sulfhydryls in chronic lung disease of the newborn

We compared the postnatal changes (days 1-28) in red blood cell glutathione and plasma sulfhydryl content in preterm babies developing chronic lung disease (CLD, n = 13) to those in babies with respiratory distress syndrome (RDS, n = 13) and control babies (n = 21). There were no initial differences in these measurements between the three groups. However, on day 28 in CLD and RDS the red blood cell glutathione was decreased compared to the control babies (p < 0.05). In CLD, there was a significant correlation between reduced/oxidized glutathione and (i) maximal FiO2 (r = -0.69, p < 0.05) and (ii) minimal a/A ratio (r = +0.73, p < 0.005). On day 28, although the plasma sulfhydryl level did not differ between the groups, the sulfhydryl/total protein ratio was decreased in CLD (p < 0.05). The late decrease in both glutathione and sulfhydryl/total protein ratio in babies with CLD suggests that oxidative stress is still ongoing at 28 days after birth and that the antioxidant capacity of their blood is still diminished at this time.     

The pulmonary effect of nitric oxide synthase inhibition following endotoxemia in a swine model

OBJECTIVE: To evaluate the pulmonary effect of treatment with N-nitro-L-arginine methyl ester (NAME) with and without inhaled nitric oxide (NO) in a swine model of endotoxemia. DESIGN: Randomized controlled trial. SETTING: Laboratory. INTERVENTIONS: Following a 20-minute intravenous infusion of Escherichia coli lipopolysaccharide (LPS) (200 micrograms/kg), animals were resuscitated with saline solution (1 mL/kg per minute) and observed for 3 hours while mechanically ventilated (fraction of inspired oxygen [FIO2], 0.6; tidal volume, 12 mL/kg; positive end-expiratory pressure, 5 cm H2O). Group 1 (LPS, n = 6) received no additional treatment; group 2 (NAME, n = 5) received NAME (3 mg/kg per hour) for the last 2 hours; group 3 (NO, n = 6) received NAME (3 mg/kg per hour) and inhaled NO (40 ppm) for the last 2 hours; and group 4 (control, n = 5) received only saline solution without LPS. MAIN OUTCOME MEASURES: Cardiopulmonary variables and blood gases were measured serially. The multiple inert gas elimination technique was performed at 3 hours. The wet-to-dry lung weight ratio was measured following necropsy. RESULTS: Administration of LPS resulted in pulmonary arterial hypertension, pulmonary edema, and hypoxemia with increased ventilation perfusion ratio mismatching. None of these changes were attenuated by NAME treatment alone but all were significantly improved by the simultaneous administration of inhaled NO. CONCLUSIONS: Systemic NO synthase inhibition failed to restore hypoxic pulmonary vasoconstriction following LPS administration. The deleterious effects of endotoxemia on pulmonary function can be improved by inhaled NO but not by systemic inhibition of NO synthase.     

Changes of vasoactive peptides and effects of inhaled nitric oxide after pneumonectomy

To clarify the role of vasoactive peptides in the physiologic response to pneumonectomy, we investigated the changes of atrial (A-type) natriuretic peptide (ANP). C-type natriuretic peptide (CNP), and endothelin-1 (ET-1) levels in the lung and blood after pneumonectomy and the effects of inhaled nitric oxide (NO; 5 ppm) after pneumonectomy in beagle dogs. The concentrations of these peptides in the lung and blood were measured by radioimmunoassay. The dogs in group A (n = 10) were observed without NO inhaling after right pneumonectomy, and the dogs in group B (n = 5) were observed with NO inhaling from 120 to 180 min after right pneumonectomy. After the thoracotomy, right lung tissue was resected for the pre-operative histological control. Tissue from the left lung was obtained at 120 min (5 dogs in group A), at 180 min (5 dogs in group A), and after 60 min of NO inhalation (group B) for the post-operative histological material. Peripheral blood was collected from the femoral artery. The pulmonary arterial pressure (PAP) was significantly increased after pneumonectomy, but rapidly decreased to the same level as the pre-operative stage after NO inhalation. Increases of plasma ANP, lung ANP and lung CNP levels occurred after pneumonectomy, while the ET-1 level was unchanged. Inhaled NO rapidly reduced the plasma ANP, lung ANP and lung CNP. These results indicate that both ANP and CNP act to maintain normotensive homeostatic balance in the pulmonary circulation.     

Successful myoblast transplantation in primates depends on appropriate cell delivery and induction of regeneration in the host muscle

In a double-blind, cross-over study, we examined the effect of inhaled budesonide (800 microgram twice daily via Turbohaler) on lung function and various markers of airway inflammation including airway responsiveness to methacholine (PC20), exhaled nitric oxide (NO), eosinophils in induced sputum, bronchoalveolar lavage (BAL), and airway biopsies from 14 patients with mild asthma needing beta2- agonist therapy only. After inhaled steroids, there was a significant increase in FEV1 and PC20, and reduction in exhaled NO. Eosinophils in induced sputum and airway biopsy sections were also significantly decreased, although BAL eosinophil counts remained unchanged. At baseline, significant correlations were observed between exhaled NO and PC20 methacholine (r = 0.64, p < 0.05), exhaled NO and peak expiratory flow rate (PEFR) variability (r = 0. 65, p < 0.05), sputum eosinophils and FEV1 (r = -0.63, p = 0.05), and sputum eosinophils and log PC20 methacholine (r = -0.67, p < 0. 05). After treatment with inhaled steroids, there was a significant correlation between eosinophils in biopsy sections, and BAL, with log PC20 methacholine. It is likely that these parameters represent different aspects of the inflammatory process, which are all inhibited by inhaled steroids.     

Susceptibility to hard metal lung disease is strongly associated with the presence of glutamate 69 in HLA-DP beta chain

Clinical, epidemiological and experimental data indicate that inhaled metal dust containing cobalt may produce an interstitial lung disease termed "hard metal disease" (HMD). Some aspects of this pathology such as the lack of correlation with dose exposure, the low frequency of the disease and the presence of T cells in the inflammation site, all suggest the existence of a genetic susceptibility, possibly to an immunological response to cobalt or to self proteins modified by cobalt. Here we report that HMD is strongly associated with residue Glu-69 of the HLA-DP beta chain. All patients, except for one with a rare genotype, possessed this marker as compared to 17 out of 35 exposed unaffected individuals (p = 0.0014). These data allow us to genetically distinguish a subgroup of cobalt-exposed individuals at risk for HMD, independently from the more common allergic reaction.     

Experimental antitumour activity of S 16020-2 in a panel of human tumours

OBJECTIVE: To compare the effects of inhaled nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO) on oxygenation, hemodynamics, and lymphatic drainage in an oleic acid lung injury model in sheep. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. ANIMALS: Thirty female sheep, weighing 35 to 40 kg. INTERVENTIONS: Acute lung injury was induced by central venous injection of oleic acid (0.5 mL/kg body weight). A chronic lymph fistula had been prepared through a right thoracotomy 3 days before the experiment. Animals were assigned randomly to the NO group (n = 14) or the ECMO group (n = 16). When a lung injury score of > 2.5 was achieved, the animals were given NO in dosage increments of 2, 5, 10, 20, and 40 parts per million (ppm), or placed on ECMO with an FIO2 of 0.21 (ECMO-21) and then 1.0 (ECMO-100) at the oxygenator. Mechanical ventilator parameters were kept constant to isolate the effects of NO and ECMO on systemic and pulmonary hemodynamics, cardiac output, oxygenation parameters, lymph/plasma protein ratio, and lymph flow. Measurements and calculations were performed after 1 hr at each individual step of NO concentration or FIO2. MEASUREMENTS AND MAIN RESULTS: In the ECMO group, PVRI and MPAP did not change and were significantly different from the NO group. In the NO group, there was a dose-dependent decrease in venous admixture, maximal at 10 ppm NO and decreasing from 40 +/- 6% to 23 +/- 10% (p < .05). This decrease was significantly different from the ECMO group, where there was no change. There was a significant increase in PaO2/FIO2 in the NO group, maximal at 10 ppm NO (84 +/- 11 to 210 +/- 90, p < .05), but a greater increase in PaO2/FIO2 on ECMO-21 (81 +/- 14 to 265 +/- 63) and a further increase on ECMO-100 (398 +/- 100) (p < .05). The lymph/plasma protein ratio remained unchanged in both groups after induction of lung injury by oleic acid. However, lymph flow decreased by 11 +/- 6% in the NO group, whereas it increased by 14 +/- 17% in the ECMO group (p < .05). CONCLUSIONS: In an oleic acid-induced sheep model of acute lung injury, there were significant differences between the effects of NO and ECMO on acute pulmonary hypertension, hypoxemia, hypercarbia, and lymph flow. NO significantly decreases pulmonary hypertension, whereas pulmonary hemodynamics were not substantially affected by ECMO. Both interventions reversed hypoxemia, but ECMO did so to a greater degree, and only ECMO improved hypercarbia. Only NO decreased lymph flow, possibly as an effect of decreased microvascular filtration pressure. This study did not attempt to evaluate the impact of these interventions on ventilatory requirements, barotrauma, or outcome. However, this model suggests that NO therapy may moderate pulmonary hypertension and improve lymph flow in acute lung injury. Clinical studies are needed to assess whether NO therapy might be beneficial in treatment of severe acute lung injury in older children and adults.     

Relationship of burn-induced lung lipid peroxidation on the degree of injury after smoke inhalation and a body burn

OBJECTIVE: We compared the effect of a modest smoke inhalation injury, a burn injury alone, and a smoke inhalation injury plus a body burn, on the degree of lung oxidant-induced lipid peroxidation and lung injury. DESIGN: Prospective animal study with concurrent controls. SETTING: An animal laboratory. SUBJECTS: Forty-four adult yearling female sheep (weight range 45 to 50 kg). INTERVENTIONS: Forty-four sheep were prepared with lung and prefemoral (soft tissue) lymph fistulas. Twelve breaths of cooled smoke with tidal volume of 10 mL/kg body weight were given to 24 sheep, producing a peak blood carboxyhemoglobin of 25% to 30%. Twelve sheep also received a 15% total body surface third-degree burn. Sheep were killed at 4 or 24 hrs. MEASUREMENTS AND MAIN RESULTS: Circulating lipid peroxidation was monitored as conjugated dienes and tracheobronchial mucosal and lung parenchyma as malondialdehyde. Antioxidant defenses were monitored by catalase activity. Lung physiologic and histologic changes were compared. We noted intense airways inflammation in both smoke inhalation groups and lung parenchymal inflammation in all groups. Lung lymph flow was modestly increased (two-fold) in the smoke inhalation groups. Alveolar water content was not significantly increased after any injury. PaO2 was decreased at 24 hrs after the smoke insult alone. Parenchymal malondialdehyde content did not increase with the smoke insult alone, but did increase from a control value of 110 +/- 20 to 270 +/- 24 nmol/g tissue by 4 hrs in the combined burn and smoke injury group, while catalase activity decreased. Airway mucosal malondialdehyde did not increase in any group. CONCLUSIONS: We conclude that alveolar capillary permeability is not increased early after a moderate smoke injury or smoke injury with burn. Lipid peroxidation is not increased in large airway or lung parenchyma with early after-smoke exposure. The addition of a burn significantly increases lung parenchymal lipid peroxidation, but the oxidant changes do not correspond with the degree of early lung dysfunction.     

The effect of inhaled nitric oxide on pulmonary ventilation-perfusion matching following smoke inhalation injury

BACKGROUND: We previously reported that inhaled nitric oxide (NO) improved pulmonary function following smoke inhalation. This study evaluates the physiologic mechanism by which inhaled NO improves pulmonary function in an ovine model. METHODS: Forty-eight hours following wood smoke exposure to produce a moderate inhalation injury, 12 animals were anesthetized and mechanically ventilated (FIO2, 0.40; tidal volume, 15 mL/kg; PEEP, 5 cm H2O) for 3 hours. For the first and third hours, each animal was ventilated without NO: for the second hour, all animals were ventilated with 40 ppm NO. Cardiopulmonary variables and blood gases were measured every 30 minutes. The multiple inert gas elimination technique (MIGET) was performed during the latter 30 minutes of each hour. The data were analyzed by ANOVA. RESULTS: Pulmonary arterial hypertension and hypoxemia following smoke inhalation were significantly attenuated by inhaled NO compared with the values without NO (p < 0.05, ANOVA). Smoke inhalation resulted in a significant increase in blood flow distribution to low VA/Q areas (VA/Q < 0.10) with increased VA/Q dispersion. These changes were only partially attenuated by the use of inhaled NO. The SF6 (sulfur hexafluoride) retention ratio was also decreased by inhaled NO. Peak inspiratory pressures and pulmonary resistance values were not affected by inhaled NO. CONCLUSIONS: Inhaled NO moderately improved VA/Q mismatching following smoke inhalation by causing selective pulmonary vasodilation of ventilated areas in the absence of bronchodilation. This modest effect appears to be limited by the severe inflammatory changes that occur as a consequence of smoke exposure.     

Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is a rare and fatal disease of unknown etiology. Inflammatory oxidant mechanisms and deficiency in nitric oxide (NO) have been implicated in the pathogenesis of pulmonary hypertension. In order to investigate abnormalities in oxidants and antioxidants in PPH, we studied intrapulmonary NO levels, biochemical reaction products of NO, and antioxidants (glutathione [GSH], glutathione peroxidase [GPx], and superoxide dismutase [SOD]) in patients with PPH (n = 8) and healthy controls (n = 8). Intrapulmonary gases and fluids were sampled at bronchoscopy. Pulmonary hypertension was determined by right-heart catheterization. NO and biochemical reaction products of NO in the lung were decreased in PPH patients in comparison with healthy controls (NO [ppb] in airway gases: control, 8 +/- 1; PPH, 2.8 +/- 0. 9; p = 0.016; and NO products [microM] in bronchoalveolar lavage fluid [BALF]: control, 3.3 +/- 1.05; PPH, 0.69 +/- 0.21; p = 0.03). However, GSH in the lungs of PPH patients was higher than in those of controls (GSH [microM] in BALF: 0.55 +/- 0.04; PPH, 0.9 +/- 0.1; p = 0.015). SOD and GPx activities were similar in the two groups (p >/= 0.50). Biochemical reaction products of NO were inversely correlated with pulmonary artery pressures (R = -0.713; p = 0.047) and with years since diagnosis of PPH (R = -0.776; p = 0.023). NO reaction products are formed through interactions between oxidants and NO, with the end products of reaction dependent upon the relative levels of the two types of molecules. The findings of the study therefore show that NO and oxidant reactions in the lung are related to the increased pulmonary artery pressures in PPH.     

Effects of inhaled versus intravenous vasodilators in experimental pulmonary hypertension

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation and improves gas exchange in acute lung failure. In experimental pulmonary hypertension, we compared the influence of the aerosolized vasodilatory prostaglandins (PG) PGI2 and PGE1 on vascular tone and gas exchange to that of infused prostanoids (PGI2, PGE1) and inhaled NO. An increase of pulmonary artery pressure (Ppa) from 8 to approximately 34 mmHg was provoked by continuous infusion of U-46619 (thromboxane A2 (TxA2) analogue) in blood-free perfused rabbit lungs. This was accompanied by formation of moderate lung oedema and severe ventilation-perfusion (V'/Q') mismatch, with predominance of shunt flow (>50%, assessed by the multiple inert gas elimination technique). When standardized to reduce the Pps by approximately 10 mmHg, inhaled NO (200 ppm), aerosolized PGI2 (4 ng x kg(-1) x min(-1)) and nebulized PGE1 (8 ng x kg(-1) x min(-1)) all reduced both pre- and postcapillary vascular resistance, but did not affect formation of lung oedema. All inhalative agents improved the V'/Q' mismatch and reduced shunt flow, the rank order of this capacity being NO > PGI2 > PGE1. In contrast, lowering of Ppa by intravascular administration of PGI2 and PGE1 did not improve gas exchange. "Supratherapeutic" doses of inhaled vasodilators in control lungs (400 ppm NO, 30 ng x kg(-1) x min(-1) of PGI2 or PGE1) did not provoke vascular leakage or affect the physiological V'/Q' matching. We conclude that aerosolization of prostaglandins I2 and E1 is as effective as inhalation of nitric oxide in relieving pulmonary hypertension. When administered via this route instead of being infused intravascularly, the prostanoids are capable of improving ventilation-perfusion matching, suggesting selective vasodilation in well-ventilated lung areas.     

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.     

Acute effects of inhaled nitric oxide in adult respiratory distress syndrome

This study evaluated the dose-response effect of inhaled nitric oxide (NO) on gas exchange, haemodynamics, and respiratory mechanics in patients with adult respiratory distress syndrome (ARDS). Of 19 consecutive ARDS patients on mechanical ventilation, eight (42%) responded to a test of 10 parts per million (ppm) NO inhalation with a 25% increase in arterial oxygen tension (Pa,O2,) over the baseline value. The eight NO-responders were extensively studied during administration of seven inhaled NO doses: 0.5, 1, 5, 10, 20, 50 and 100 ppm. Pulmonary pressure and pulmonary vascular resistance exhibited a dose-dependent decrease at NO doses of 0.5-5 ppm, with a plateau at higher doses. At all doses, inhaled NO improved O2 exchange via a reduction in venous admixture. On average, the increase in Pa,O2, was maximal at 5 ppm NO. Some patients, however, exhibited maximal improvement in Pa,O2 at 100 ppm NO. In all patients, the increase in arterial O2 content was maximal at 5 ppm NO. The lack of further increase in arterial O2 content above 5 ppm partly depended on an NO-induced increase in methaemoglobin. Respiratory mechanics were not affected by NO inhalation. In conclusion, NO doses < or =5 ppm are effective for optimal treatment both of hypoxaemia and of pulmonary hypertension in adult respiratory distress syndrome. Although NO doses as high as 100 ppm may further increase arterial oxygen tension, this effect may not lead to an improvement in arterial O2 content, due to the NO-induced increase in methaemoglobin. It is important to consider the effect of NO not only on arterial oxygen tension, but also on arterial O2 content for correct management of inhaled nitric oxide therapy.     

The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer

METHODS: Three hundred forty-two patients with lung cancer and 99 patients with nonneoplastic lung diseases (control group) underwent intraoperative pleural lavage with 300 ml physiologic saline solution before (lavage I) and after resection (lavage II). RESULTS: Studies of the lavage fluid in all control patients were negative, that is, there were no false positive findings. Tumor cells were found in lavage I in 132 patients (38.6%) and also in lavage II in 99 of them. In stage I (pT1 N0, pT2 N0) lung cancer, tumor cell detection was possible in 47 patients (28.6%). The 4-year survival of patients with resected non-small-cell lung cancer was 24% (95% confidence interval, 16% to 32%) if lavage I results were positive and 52% (95% confidence interval, 45% to 59%) if lavage I results were negative (all stages, p = 0.007). For patients with stage I disease (n = 164) the 4-year survival was 35% (95% confidence interval, 18% to 52%) if lavage I results were positive (n = 47), and 69% (95% confidence interval, 60% to 78%) if lavage I results were negative (n = 117) (p = 0.037). On multivariate analysis the positive cytologic result in intraoperative pleural lavage was an additional prognostic factor for our patients. To prove how the tumor cells enter the pleural cavity, we performed tissue cultures of tumor-free parenchyma in 23 cases of lung cancer. Tumor cell detection by histology and immunohistology was possible in 16 cases (69.6%). Detection of tumor cells in pleural lavage fluid before resection proves that tumor cells have spread into the pleural cavity. CONCLUSION: The positive result in pleural lavage seems to be a prognostic predictor for patients with lung cancer.     

Antioxidant defenses in lung lining fluid of broilers: impact of poor ventilation conditions

Lung lining fluid antioxidants represent a potentially important protective barrier of lung epithelial cells to damaging effects of air pollutants, yet no information is apparently available concerning lung lining fluid antioxidants in broilers. Therefore, goals of this study were to establish uric acid, ascorbic acid, reduced (GSH) and oxidized (GSSG) glutathione, and protein concentrations in lung lining fluid obtained from male broiler chickens maintained for 6 to 7 wk within environmentally controlled rooms (Control) or chronically exposed to high levels of dust and ammonia within a broiler rearing house (House). The entire respiratory tract was carefully removed following an overdose of anesthetic and lavage fluid was collected after flushing the lungs with heparin-saline (10 mL per lung). There was no difference in GSH, but GSSG, uric acid, and protein concentrations were higher in House birds than in Controls. An increase in the GSSG to total glutathione (GSx) ratio, an indicator of oxidative stress, was also observed in birds maintained in the House environment. Ascorbic acid was not detected in House-reared birds and detected in only 4 of 12 Controls. Regression analysis revealed positive correlations between lung lining fluid protein and uric acid (r = 0.71; P < 0.01), protein and GSSG (r = 0.73; P < 0.01), and uric acid and GSSG concentrations (r = 0.69, P < 0.01). Additionally, GSSG was positively correlated (r = 0.66; P < 0.01) with the right ventricular weight ratio, an index commonly used in identifying the development of pulmonary hypertension syndrome in broilers. These data, the first to document lung lining fluid antioxidants in avian species, indicate an oxidative stress can be detected in fluid of broilers exposed to high levels of dust and ammonia in a simulated poultry house environment.     

Abdominal findings in AIDS-related pulmonary tuberculosis correlated with associated CD4 levels

BACKGROUND: There is evidence that inducible nitric oxide (NO) may be directly related to the process of allograft rejection. Because of its strong pulmonary vasodilatory activity, inhaled NO (INO) has recently been used as a therapeutic option for allograft dysfunction after lung transplantation. The action of inducible NO and inhaled NO seems contradictory for preserving posttransplantation pulmonary allograft function. INO used for lung transplant recipients may actually enhance acute allograft rejection. We studied the effect of INO on acute allograft rejection with a rat pulmonary allograft model. METHOD: A total of 24 left lung allotransplantations were performed from Lewis donors into F344 recipients. Animals were divided into two groups and inhaled either room air alone or 20 ppm NO with room air in a closed chamber immediately after transplantation until rats were killed on days 7 and 14. During observation, NO uptake was monitored by measuring serum NO2-/NO3- level. Acute rejection was evaluated by use of a semiquantitative radiographic scoring method (aeration score: 0 to 6, opaque to normal appearance) and rejection score (0 to 4, no sign of rejection to diffuse mononuclear infiltration). RESULTS: Markedly elevated serum NO2-/NO3- levels were observed in the NO inhalation group compared with levels in the normal air inhalation control group (110.8 +/- 25.3 vs 16.3 +/- 4.0 micromol/L/ml on day 7, p < 0.01; 107.0 +/- 30.9 vs 16.8 +/- 4.8 micromol/L/ml on day 14, p < 0.01). However, no positive effect of INO on acute rejection was found histologically or radiographically. CONCLUSION: The effect of INO on acute rejection is likely so minimal as not to be clinically relevant.     

Circulating markers of oxidative stress are raised in normal pregnancy and pre-eclampsia

OBJECTIVE: To determine whether circulating markers of oxidative stress are elevated in pre-eclampsia when appropriate precautions are taken to prevent in vitro oxidation DESIGN: A prospective study. SETTING: Nuffield Department of Obstetrics and Gynaecology, Oxford and The William Harvey Institute, London. SAMPLE: Three groups of women: those with pre-eclampsia (n = 19), control pregnant women (n = 19) matched for gestation, age and parity and a group of non pregnant individuals of reproductive age (n = 7). METHODS: Citrated plasma was stored at -80 degrees C with 20 micromol beta hydroxytoluene to prevent auto-oxidation. Plasma samples were assayed for levels of 8 epi-prostaglandin F2alpha, lipid hydroperoxides, malondialdehyde and also the lipid soluble antioxidant vitamin E. RESULTS: There were no differences in 8 epi-prostaglandin F2alpha, lipid peroxide or malondialdehyde levels between the groups of women with pre-eclampsia and those acting as pregnant controls. However, lipid hydroperoxides and malondialdehyde were significantly raised in both pre-eclampsia and normal pregnancy, compared with nonpregnant women. Vitamin E levels were similar in women with pre-eclampsia and those with a normal pregnancy, but in both groups levels were significantly higher than in nonpregnant women. CONCLUSION: Circulating markers of oxidative stress are raised in normal pregnancy and pre-eclampsia.