Plasma proteins modified by tyrosine nitration in acute respiratory distress syndrome.
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The present study identifies proteins modified by nitration in the plasma of patients with ongoing acute respiratory distress syndrome (ARDS). The proteins modified by nitration in ARDS were revealed by microsequencing and specific antibody detection to be ceruloplasmin, transferrin, alpha(1)-protease inhibitor, alpha(1)-antichymotrypsin, and beta-chain fibrinogen. Exposure to nitrating agents did not deter the chymotrypsin-inhibiting activity of alpha(1)-antichymotrypsin. However, the ferroxidase activity of ceruloplasmin and the elastase-inhibiting activity of alpha(1)-protease inhibitor were reduced to 50.3 +/- 1.6 and 60.3 +/- 5.3% of control after exposure to the nitrating agent. In contrast, the rate of interaction of fibrinogen with thrombin was increased to 193.4 +/- 8.5% of the control value after exposure of fibrinogen to nitration. Ferroxidase activity of ceruloplasmin and elastase-inhibiting activity of the alpha(1)-protease inhibitor in the ARDS patients were significantly reduced (by 81 and 44%, respectively), whereas alpha(1)-antichymotrypsin activity was not significantly altered. Posttranslational modifications of plasma proteins mediated by nitrating agents may offer a biochemical explanation for the reported diminished ferroxidase activity, elevated levels of elastase, and fibrin deposits detected in patients with ongoing ARDS. (+info)
Carbon dioxide enhances nitration of surfactant protein A by activated alveolar macrophages.
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We assessed whether reactive oxygen-nitrogen intermediates generated by alveolar macrophages (AMs) oxidized and nitrated human surfactant protein (SP) A. SP-A was exposed to lipopolysaccharide (100 ng/ml)-activated AMs in 15 mM HEPES (pH 7.4) for 30 min in the presence and absence of 1.2 mM CO(2). In the presence of CO(2), lipopolysaccharide-stimulated AMs had significantly higher nitric oxide synthase (NOS) activity (as quantified by the conversion of L-[U-(14)C]arginine to L-[U-(14)C]citrulline) and secreted threefold higher levels of nitrate plus nitrite in the medium [28 +/- 3 vs. 6 +/- 1 (SE) nmol. 6.5 h(-1). 10(6) AMs(-1)]. Western blotting studies of immunoprecipitated SP-A indicated that CO(2) enhanced SP-A nitration by AMs and decreased carbonyl formation. CO(2) (0-1.2 mM) also augmented peroxynitrite (0.5 mM)-induced SP-A nitration in a dose-dependent fashion. Peroxynitrite decreased the ability of SP-A to aggregate lipids, and this inhibition was augmented by 1.2 mM CO(2). Mass spectrometry analysis of chymotryptic fragments of peroxynitrite-exposed SP-A showed nitration of two tyrosines (Tyr(164) and Tyr(166)) in the absence of CO(2) and three tyrosines (Tyr(164), Tyr(166), and Tyr(161)) in the presence of 1.2 mM CO(2). These findings indicate that physiological levels of peroxynitrite, produced by activated AMs, nitrate SP-A and that CO(2) increased nitration, at least partially, by enhancing enzymatic nitric oxide production. (+info)
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.
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BACKGROUND: Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. METHODS: Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. RESULTS: The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water (P<0.001), respectively. CONCLUSIONS: In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use. (+info)
Respiratory and haemodynamic effects of the prone position at two different levels of PEEP in a canine acute lung injury model.
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This study was designed to examine whether the oxygenation response in the prone position differs in magnitude depending on the level of positive end-expiratory pressure (PEEP) applied in the supine position, and whether cardiac output (CO) increases in the prone position. In seven supine dogs, acute lung injury was established by saline lavage (arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) 17.8+/-9.6 kPa (134+/-72 mmHg)), and inflection point (Pflex) of the respiratory system was measured (6.6+/-1.4 cmH2O). Pa,O2/FI,O2 and CO of the supine and prone positions were obtained under the application of low PEEP and then under optimal PEEP (2 cmH2O below and above Pflex, respectively). The net increase in Pa,O2/FI,O2 by prone positioning was greater at low PEEP (27.3+/-12.0 kPa (205+/-90 mmHg)) than at optimal PEEP (4.4+/-13.0 kPa (33+/-98 mmHg)) (p=0.006). CO decreased significantly with optimal PEEP in the supine position (2.4+/-0.5 versus 3.1+/-0.4 L x min(-1) at baseline, p<0.001), and increased to 3.4+/-0.6 and 3.6+/-0.7 L x min(-1) in the prone position at 5 min and 30 min, respectively (both p=0.018). When the dogs were turned supine at optimal PEEP, CO again decreased (2.4+/-0.5 L x min(-1), p<0.001). In conclusion, the prone position augmented the effect of relatively low positive end-expiratory pressure on oxygenation, and attenuated the haemodynamic impairment of relatively high positive end-expiratory pressure in a canine acute lung injury model. (+info)
Oxidatively modified proteins in bronchoalveolar lavage fluid of patients with ARDS and patients at-risk for ARDS.
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Oxidative stress in acute respiratory distress syndrome (ARDS) is considered as an important pathophysiological mechanism in acute impairment of lung function. The present study investigated whether a pulmonary oxidant-antioxidant imbalance is indicated by substantial oxidative modification of proteins in bronchoalveolar lavage (BAL) fluid. Oxidatively modified proteins in BAL fluid, as measured by the reduction of protein carbonyl groups with tritiated borohydride, were studied in control subjects, patients with clinically established ARDS, and patients considered at-risk for ARDS because they had had coronary bypass surgery. Subsets of these at-risk patients were pretreated either with methylprednisolone or N-acetylcysteine. The carbonyl content of BAL fluid proteins was greatly increased in ARDS patients (5.0+/-13 nmol carbonyl x mL(-1) BAL fluid; mean+/-SEM; p=0.0004; n=10) and moderately increased in the untreated patients at-risk for ARDS (1.3+/-0.2 nmol x mL(-1); p=0.027; n=19) compared with controls (0.8+/-0.2 nmol x mL(-1); n=12). The two other at-risk groups pretreated either with methylprednisolone or N-acetylcysteine showed carbonyl values that were statistically not different from the controls (1.2+/-0.2 nmol x mL(-1); p=0.13; n=13, and 1.1+/-0.3 nmol x mL(-1); p=0.40; n=8, respectively). These results show that oxidatively modified proteins clearly accumulated in bronchoalveolar lavage fluid of acute respiratory distress syndrome patients, and to a minor extent in untreated at-risk patients. These data suggest a severe oxidant-antioxidant imbalance in acute respiratory distress syndrome. (+info)
G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome.
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Activated neutrophils play a major role in the pathogenesis of acute respiratory distress syndrome (ARDS), and persistence of pulmonary neutrophilia is related to poor survival. Interleukin (IL)-8 is implicated in recruiting neutrophils to the lungs but it has been postulated that granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), which can promote the survival of neutrophils by delaying apoptosis, may prolong the inflammatory response. The aim of this study was to investigate the levels of GM-CSF and G-CSF in the lungs of patients with ARDS and determine their relationship relative to IL-8 with levels of neutrophils and clinical outcome. The lungs of 31 patients with ARDS were sampled by means of bronchoalveolar lavage (BAL) and assays of the three cytokines were conducted via enzyme-linked immunosorbent assay. GM-CSF, G-CSF and IL-8 were all increased in the patients compared to healthy controls but concentrations of GM-CSF were much lower than those of G-CSF and IL-8 (GM-CSF+info)
Group IIA phospholipase A2 mediates lung injury in intestinal ischemia-reperfusion.
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OBJECTIVE: To assess the mechanistic role of group IIA phospholipase A2 (PLA2) in the process of local and distant organ injury after intestinal ischemia-reperfusion. SUMMARY BACKGROUND DATA: Intestinal ischemia-reperfusion produces lung injury by a mechanism that involves PLA2 activation, but it is unclear which isozyme is responsible for this phenomenon. Group IIA PLA2, one of the secreted forms of PLA2, is known to play a pivotal role in a variety of inflammatory reactions. METHODS: Rats underwent 45 minutes of superior mesenteric artery occlusion in the presence and absence of pretreatment with group IIA PLA2 inhibitor, S-5920/LY315920Na (20 mg/kg, subcutaneously, 30 minutes before clamping). At 2 hours of reperfusion, intestinal and lung leak was assessed by 125I-albumin tissue/blood ratio, and liver injury was estimated by serum alanine aminotransferase. PLA2 activities in tissues and sera were quantitated by phosphatidyl-glycerol/sodium cholate mixed micelle assay. PLA2 activities in tissues were also measured after in vitro preincubation with EDTA, S-5920/LY315920Na, or antirat group IIA PLA2 antibody. RESULTS: Intestinal ischemia-reperfusion provoked intestinal leak, liver injury, and lung leak, whereas tissue PLA2 activity was decreased in the intestine, unchanged in the liver, and increased in the lung. Serum PLA2 activities were increased in the portal and systemic circulation during ischemia. Pretreatment with S-5920/LY315920Na eliminated PLA2 activities in all tissues and sera and only abolished lung leak. The in vitro experiment revealed that most of the intestinal and lung PLA2 activities were inhibited by EDTA, S-5920/LY315920Na, and antirat group IIA PLA2 antibody, but hepatic PLA2 activity was not. CONCLUSION: Intestinal ischemia-reperfusion appears to produce lung injury by a mechanism that involves group IIA PLA2 activation. Intestinal ischemia-reperfusion is likely to promote intestinal and hepatic injury independent of group IIA PLA2. (+info)
Diagnosis of pneumothorax in critically ill adults.
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The diagnosis of pneumothorax is established from the patients' history, physical examination and, where possible, by radiological investigations. Adult respiratory distress syndrome, pneumonia, and trauma are important predictors of pneumothorax, as are various practical procedures including mechanical ventilation, central line insertion, and surgical procedures in the thorax, head, and neck and abdomen. Examination should include an inspection of the ventilator observations and chest drainage systems as well as the patient's cardiovascular and respiratory systems.Radiological diagnosis is normally confined to plain frontal radiographs in the critically ill patient, although lateral images and computed tomography are also important. Situations are described where an abnormal lucency or an apparent lung edge may be confused with a pneumothorax. These may arise from outside the thoracic cavity or from lung abnormalities or abdominal viscera inside the chest. (+info)