Intravascular FC-77 attenuates phorbol myristate acetate-induced acute lung injury in isolated rat lungs.

OBJECTIVE: To evaluate whether intravascular Fluorinert (FC-77) attenuates phorbol myristate acetate (PMA)-induced acute lung injury in rats. DESIGN: Randomized, controlled animal study. SETTING: Animal care facility procedure room in a medical center. SUBJECTS: Thirty-six adult male Sprague-Dawley rats each weighing 250-350 g. INTERVENTIONS: PMA (2 microg/kg) was injected into lung perfusate and induced acute lung injury. Different doses of FC-77 were given before PMA administration. The isolated rat lungs were randomly assigned to two control groups (saline and 1% FC-77 only) and four PMA groups (PMA, 0.1% FC-77 + PMA, 0.5% FC-77+PMA, and 1% FC-77+PMA); each condition was maintained for 60 mins. MEASUREMENTS AND MAIN RESULTS: The extent of acute lung injury was assessed by microvascular permeability (measured using the capillary filtration coefficient), lung weight gain, wet lung-to-body weight ratio, pulmonary arterial pressure, and protein concentration of the bronchoalveolar lavage fluid. The concentration of tumor necrosis factor-alpha in lung perfusate was determined. Parts of the right lung were excised for myeloperoxidase and malondialdehyde measurements, whereas the rest was examined for histopathological changes. PMA produced a significant increase in the capillary filtration coefficient, lung weight gain, wet lung-to-body weight ratio, pulmonary arterial pressure, and protein concentration of the bronchoalveolar lavage fluid. Tumor necrosis factor-alpha in lung perfusate and myeloperoxidase and malondialdehyde in lung tissue were also significantly increased. In addition, the pathologic picture showed increased neutrophil infiltration in lung tissues. In contrast, pretreatment with intravascular FC-77 significantly attenuated these variables in a dose-dependent manner compared with the PMA group. CONCLUSIONS: Intravascular FC-77 significantly ameliorated acute lung injury induced by PMA in rats in a dose-dependent manner. The protective mechanism may act, in part, by decreasing neutrophil infiltration, inhibiting proinflammatory cytokine production, and preventing the release of free radicals.

Oxidative stress and erythropoietin response in altitude exposure.

PURPOSE: Oxidative stress and erythropoietin (EPO) levels are increased following high altitude exposure. We hypothesized that the altitude-oxidative stress and EPO response would be associated with the presence or absence of acute mountain sickness (AMS) in subjects exposed at high altitude. METHODS: The study enrolled 29 healthy volunteers exposed at altitudes without strenuous physical exercise. Oxidative stress was determined by the spectrophotometric measurement of the colour occurring during the reaction of malondialdehyde (MDA) with thiobarbituric acid (TBA) on blood samples. Ferritin and EPO were also measured simultaneously. RESULTS: During a rise in altitude at 2000 and 3000 m, there were no changes in plasma ferritin level in either of the 2 groups with or without AMS. In contrast, EPO increased at an altitude of 3000 m and after returning to sea level (28.2+/-2.7, 26.9+/-3.3 vs 12.2+/-1.4 and 17.1+/-1.6, P < 0.05, in group without AMS; 29.3+/-4.5, 22.8+/-2.7 vs 10.6+/-1.0 and 16.1+/-1.5, # P < 0.05, in group with AMS; compared with the baseline level and at the height of 2000 meters). At a height of 3000 m, plasma MDA level was elevated compared with that at the altitude of baseline and 2000 m in both groups of subjects with and without AMS (3.77+/-0.29 vs 1.14+/-0.17, and 1.64+/-0.22, P < 0.001, in subjects with AMS; 3.65+/-0.39 vs 1.71+/-0.21, and 1.73+/-0.21, P < 0.001, in subjects without AMS) . After returning to sea level, subjects without AMS had lower MDA oxidative stress compared with those with AMS (2.58+/-0.26 vs 3.51+/-0.24, P = 0.0223). Along with a rise in altitude, the oxidative stress in these both groups was not correlated with the changes in EPO (r2 = 0.0728, P = 0.1096). CONCLUSION: High altitude-induced oxidative stress, detected by MDA assay, is not different between the two groups of subjects with and without AMS. Upon return to sea level, subjects without AMS had lower MDA oxidative stress burden and higher EPO level than those with AMS. Whether the subjects with altitude illness had delayed recovery from oxidative stress merits further investigation.

Hemorrhage from an enlarged emphysematous bulla during commercial air travel.

Pulmonary bullae are a common late complication in patients with emphysema. Non-communicating emphysematous bullae may expand during air travel when the ambient pressure is reduced, resulting in various forms of barotrauma including pneumothorax and air embolism. We report a 62-yr-old man with emphysema who developed hemoptysis during international commercial air travel. CT scan of the chest obtained after the travel showed air-fluid level in an enlarged bulla. He underwent resection of the bulla and had a full recovery. This is a unique presentation of stretch injury of a bulla as a form of pulmonary barotrauma occurring during commercial air travel. With the most recent ruling by the Federal Aviation Administration to allow patients with advanced chronic obstructive lung disease to travel by air with their own supplemental oxygen devices, physicians need to be aware of this type of pulmonary barotrauma and properly advise such patients who are planning to travel by air.

Role of open lung biopsy in patients with diffuse lung infiltrates and acute respiratory failure.

BACKGROUND AND PURPOSE: Open lung biopsy (OLB) is the standard procedure for the diagnosis of specific parenchymal lung diseases. The purpose of this study was to investigate the influence of OLB on subsequent treatment strategy and outcome in patients with diffuse lung infiltrates and acute respiratory failure. METHODS: This retrospective review included 32 patients (aged 50.6 +/- 21.7 years) with acute respiratory failure and diffuse pulmonary infiltrates who underwent OLB from 1990-2002. Data analyzed included diagnoses, treatment alterations, 30-day survival, oxygenation status, and histologic results. RESULTS: Specific diagnoses were made in 53.1% of patients (17/32), 23 (71.9%) of whom had acute respiratory distress syndrome (ARDS). Diagnostic yields did not differ with immunity status or ARDS. OLB led to specific decisions of treatment in 46.9% of patients (15/32), and only 7 of these 32 patients (21.8%) survived. Overall mortality was 56.2% (18/32) and was not influenced by pre-OLB oxygenation or histologic results. Although perioperative complications affected 40.6% of patients (13/32), none of the deaths were surgery-related. Complication rates were significantly higher in patients with ARDS (p = 0.04). CONCLUSIONS: OLB is associated with a low perioperative mortality rate and acceptable morbidity rate in patients with diffuse lung infiltrates and acute respiratory failure, including those patients with ARDS. In this study, a specific diagnosis was obtained by OLB in more than half of patients with diffuse pulmonary infiltrates and ARDS. In addition, OLB resulted in either use of a new therapeutic strategy or elimination of unnecessary treatment in nearly one-half of patients (46.9%).

Evaluation of risk factors for asthma in Taipei City.

BACKGROUND: Asthma has rarely been studied by evaluating all of its trigger factors in 1 study population. Thus, correlations between the concentration of allergen immunoglobulin (Ig) E antibodies and airway limitation or asthma severity remain unclear. METHODS: Five hundred and seventy-nine asthmatic patients were enrolled, and serum specific IgE antibodies to allergens were analyzed. All suspected trigger factors were assessed by questionnaire, case histories over a 4-year period, and diary card recordings; possible trigger factors were then re-evaluated. RESULTS: Antibodies to the following allergens were found: Dermatophagoides pteronyssinus (59.8% of patients), D. microceras (58.8%), D. farinae (56.8%), cockroach (38.3%), dog dander (26.3%), Candida albicans (13.3%), cat dander (10%), and Cladosporium herbarum (6.6%). A greater prevalence of allergy to dog and cat dander was found than previously. Younger patients were more often positive for mite allergens, and had higher titers of antibodies against such allergens, than older patients. Further, females had a lower concentration of mite allergen antibodies than males. No correlation between the concentration of allergen antibodies and forced expiratory volume in 1 second (FEV1), or the ratio of FEV1:forced vital capacity (FEV1:FVC), was found. In addition, there was no significant change in antibody titers with varying asthma severity. Non-allergenic trigger factors were irritant air inhalants (94.6% of patients), respiratory infection (92.2%), exercise (75.2%), emotional factors (58.8%), drugs and chemical substances (16%). CONCLUSION: There are multiple trigger factors in asthma. Allergenic trigger factors are more common in younger than older patients, whereas non-allergenic trigger factors are more common in older patients. There was no linear correlation between the concentration of specific IgE antibodies and asthma severity or airway limitation; therefore, to prevent asthma attacks in individual asthmatic patients, greater attention should be paid to avoiding all potential trigger factors, and not just house dust mite allergens.

Effect of ascorbic acid administration in hemodialysis patients on in vitro oxidative stress parameters: influence of serum ferritin levels.

BACKGROUND: Ascorbic acid supplementation has been recommended to circumvent resistance to erythropoietin, which sometimes occurs in iron-overloaded uremic patients. In considering the pro-oxidant effect of ascorbic acid, the authors hypothesize that adjuvant therapy with larger doses of ascorbic acid in hemodialysis patients with iron overload may raise the risk of increasing free radical generation. The oxidative stress of intravenous ascorbic acid supplementation in hemodialysis patients was evaluated in this study. METHODS: Six healthy subjects and 29 hemodialysis patients were enrolled. Chemical scavenging activity of various compounds was measured by in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Free radical generation was determined in vitro by lucigenin-enhanced chemiluminescence (LucCL) assay on blood samples. Blood biochemistries were also measured simultaneously in hemodialysis patients 1 minute before and 5 minutes later in the presence or absence of intravenous injection of 300 mg ascorbic acid. RESULTS: Ascorbic acid presented a strong antioxidant effect in DPPH chemical reaction. On the contrary, it exerted pro-oxidant effect when mixed with plasma or whole blood of healthy subjects and hemodialysis patients. The pro-oxidant effect of ascorbic acid detected by LucCL was attenuated by various iron chelators and superoxide dismutase. In hemodialysis patients, the changes of LucCL intensity were significantly higher in the ascorbic acid-treated group than those in the control group (1261.0 +/- 401.9 v 77.4 +/- 62.5 relative light unit [RLU]; P < 0.05). Adjuvant ascorbic acid therapy resulted in significantly higher LucCL intensity in hemodialysis patients with ferritin > or =600 ng/mL (1,348.2 pmol/L) than those with ferritin less than 600 ng/mL (2,296.0 +/- 763.8 v 414.3 +/- 88.0 RLU; P<0.05). The changes of LucCL intensity were positively correlated with serum ferritin level (R2=0.8673; P<0.05). However, there was no significant correlation between the responses of LucCL intensity to ascorbic acid administration and transferrin saturation (R2=0.195; P=0.0665). CONCLUSION: Persons with excess ascorbic acid supplement in the blood or plasma generate iron-chelator-suppressible chemiluminescents suggestive of free radical formation. Whether the findings occur in vivo or that the free radicals generated in vitro lead to toxicity in patients is not known from this study. These results suggest that either lower parenteral dose or lower infusion rate of ascorbic acid may be more appropriate for adjuvant therapy in iron-overloaded uremic patients.

Echogenic swirling pattern as a predictor of malignant pleural effusions in patients with malignancies.

OBJECTIVES: Chest ultrasonography is a useful diagnostic tool for the detection of pleural effusions of different etiologies. Our purpose was to determine whether the echogenic swirling pattern identifiable on real-time chest ultrasonographic images is a predictor of malignant pleural effusions in patients with malignancies. DESIGN: Medical records of patients undergoing chest ultrasonography in the Tri-Service General Hospital (Taiwan) between January 2000 and December 2002 were reviewed retrospectively. Patients with an echogenic swirling pattern in the pleural effusion, or with malignant diseases associated with pleural effusions, whose pleural fluids had been examined cytologically or whose pleural tissues had been examined pathologically, were enrolled in this study (n = 140). Malignant pleural effusions were defined by the presence of malignant cells in the pleural fluid identified by thoracentesis or by pleural biopsy. The echogenic swirling pattern was defined as numerous echogenic floating particles within the pleural effusion, which swirled in response to respiratory movement or heartbeat. Correlation between malignant pleural effusions and the echogenic swirling pattern was compared in patients with an underlying malignant disease. RESULTS: In patients with underlying malignancies, malignant pleural effusions were diagnosed in 81.8% of patients with a positive echogenic swirling pattern and in 48% of those with no echogenic swirling pattern. The presence of echogenic swirling was significantly more predictive of malignant pleural effusions than was the absence of echogenic swirling (p < 0.01). CONCLUSIONS: The echogenic swirling pattern is a useful predictor of possible malignant pleural effusions, and may be a good marker for malignant pleural effusions in patients with underlying malignancies.

Baicalin attenuates air embolism-induced acute lung injury in rat isolated lungs.

BACKGROUND AND PURPOSE: Baicalin has been reported to have anti-inflammatory effects and protect against various tissue injuries. However, the effect of baicalin on air embolism-induced acute lung injury has not been tested yet. EXPERIMENTAL APPROACH: Acute lung injury was induced by infusion of air at a rate of 0.25 mL.min(-1) for 1 min into the pulmonary artery of rat isolated lungs. At the end of the experiment, samples were collected for assessment of lung injury, biochemical analysis and histology. Different doses of baicalin (1, 2 and 4 mg.kg(-1)) were given into the perfusate before air infusion. KEY RESULTS: Air embolism elicited a significant increase in microvascular permeability (K(f)), lung weight gain, wet/dry weight ratio, pulmonary artery pressure and protein concentration in the bronchoalveolar lavage fluid. Levels of the cytokines, tumour necrosis factor alpha and cytokine-induced neutrophil chemoattractant-1 in perfusate, and malondialdehyde levels and myeloperoxidase activities in lung tissue were also significantly increased. In addition, histological examination showed increased neutrophil infiltration in lung tissues. Furthermore, nuclear factor-kappaB activity and degradation of IkappaB-alpha were significantly increased in lungs. Pretreatment of the lungs with baicalin (4 mg.kg(-1)) showed a statistically significant difference in all of the assessed parameters, except for alteration in the pulmonary artery pressure. CONCLUSIONS AND IMPLICATIONS: Our study suggests that baicalin attenuated air embolism-induced acute lung injury and may be considered a useful adjunct drug therapy in this clinical condition.

JNK signaling pathway is required for bFGF-mediated surface cadherin downregulation on HUVEC.

Angiogenesis, the process of new blood vessel formation, is important in wound healing, inflammation, tumorigenesis and metastases. During this process, it is a critical step of the loosening of cellular interactions between endothelial cells, which are dependent on the architecture of adherens junction constructed by homophilic interactions of cell surface cadherins. Several studies suggested that the dynamic changes of cadherins are necessary during angiogenesis. However, the mechanism of cadherins regulation on endothelial cells requires further delineation. Here, we showed that basic fibroblast growth factor (bFGF), a pivotal pro-angiogenic factor, can downregulate typical cadherins (E-, N-, P- and VE-cadherin) expression on the surface of human umbilical vein endothelial cells (HUVECs) via FGF receptor 1 (FGFR1) signaling. The bFGF-mediated surface cadherin downregulation was significantly reversed only when the HUVECs were treated with JNK inhibitor (SP600125), but not ERK (PD98059) or p38 inhibitor (SB203580). Infecting HUVECs with a dominant negative H-Ras mutant (Ras(S17N)) interferes bFGF-mediated cadherin downregulation, and the result suggests that bFGF attenuates surface cadherin expression on HUVECs via FGFR1 and intracellular Ras-JNK signaling. However, after growth factors withdrawal, FGFR1 blockade or JNK inhibition for 16 h, cadherins were re-expressed on cell surface of HUVECs. But the mRNA or total protein of cadherins had no significant change, suggesting that the effect of bFGF on cadherin expression may work through a post-translational control. Our data first suggest that JNK participates in bFGF-mediated surface cadherin downregulation. Loss of surface cadherins may affect the cell-cell interaction between endothelial cells and facilitate angiogenesis.

L-Arginine prevents air embolism-induced acute lung injury in rats.

OBJECTIVE: Pulmonary air embolism, causing vessel obstruction and primary or secondary reactions of blood, can lead to acute lung injury. In addition, nitric oxide has been known to play a key role in various causes of lung injury. In this study we employed the isolated rat lung model to investigate the effects of l-arginine on air embolism-induced lung injury. DESIGN: Randomized, controlled study. SETTING: Animal-care facility procedure room. SUBJECTS: Forty-two adult male Sprague-Dawley rats each weighing 250-350 g. INTERVENTIONS: Infusion of air at the rate of 0.25 mL/min for 1 min into the pulmonary artery in isolated and perfused rat lung resulted in pulmonary hypertension and lung edema. Air embolism elicited a significant increase in microvascular permeability as measured by the capillary filtration coefficient, lung weight gain, lung weight-to-body weight ratio, pulmonary arterial pressure, and protein concentration of bronchoalveolar lavage fluid. MEASUREMENTS AND MAIN RESULTS: Pretreatment with L-arginine (4 mmol/L) significantly attenuated the acute lung injury induced by air embolism as shown by a significant decrease in all of the assessed variables but did not alter the pulmonary arterial pressure (p < .05). The protective effect of l-arginine was blocked when N(G)-nitro-L-arginine methyl ester (5 mmol/L) was added. Pretreatment with N(G)-nitro-L-arginine methyl ester exacerbated air embolism-induced lung injury. CONCLUSIONS: Our findings suggest that L-arginine can prevent air embolism-induced lung injury.

Association of in vitro oxidative stress, serum ferritin concentration and C-reactive protein in febrile emergency room patients.

BACKGROUND: Both C-reactive protein (CRP) and ferritin have been reported to reflect the extent of oxidative stress and inflammation in individual patients and may be useful markers of disease activity and mortality risk. Exposure to oxidative stress has been reported to increase ferritin synthesis. We investigated the relationship between oxidative stress with CRP and ferritin concentrations in febrile emergency room patients to test the hypothesis whether the intensity of oxidative stress correlated with serum ferritin concentration. METHODS: Six normal healthy volunteers and 59 emergency room, febrile patients with body temperature >38.3 we enrolled before receiving medical treatment. Baseline measurements included complete blood count, blood biochemistry, CRP and serum ferritin concentrations, and transferring saturation (TSAT). The intensity of lucigenin-enhanced chemiluminescence (LucCL), corresponding to the level of superoxide, was detected by luminometer. RESULTS: In febrile patients, plasma LucCL intensity was higher than in normal healthy volunteers (P<0.05). The group with bacterial infection had higher serum ferritin (319.4+/-53.7 vs 102.0+/-21.2 ng/dL, P<0.05) and CRP concentrations (7.2+/-1.2 vs 2.2+/-0.6 mg/dL; P<0.05) than the group without bacterial infection. There were no differences in leukocytes (9790+/-606 vs 9577+/-656 /mm3) or plasma LucCL intensity (423.7+/-10.8 vs 409.5+/-6.9 relative light unit?RLU?;) between the two groups. LucCL intensity showed no correlation with serum ferritin concentration (r= -0.0599, P>0.05), TSAT(r= -0.0592, P>0.05), CRP(r= 0.1027, P>0.05) and absolute neutrophil counts (r= 0.1059; P >0.05). CONCLUSION: In this sample of emergency room febrile patients, plasma LucCL intensity was higher than in normal healthy control volunteers. A single point measurement of oxidative stress, particularly plasma LucCL intensity, may not be sufficient to differentiate the origin of fever in febrile patients. These data demonstrate that patients with bacterial infection had increased levels of CRP and ferritin, but this was not associated with LucCL intensity.

The protective effect of adenosine triphosphate-MgCl2 on ischemia-reperfusion lung injury is leukocyte dependent.

Adenosine triphosphate (ATP)-MgCl(2) attenuates ischemia-reperfusion (I-R)-induced lung injury in rats. A previous study indirectly suggests that Mg(2+)-dependent ecto-ATPases on the surface of leukocytes are responsible for the hydrolysis of ATP-MgCl(2) to adenosine, which then contributes to the protective effect of ATP-MgCl(2). This study investigated the role of leukocytes in I-R injury and the protective effect of ATP-MgCl(2) in our buffer-perfused isolated rat lung model. After isolating the lung blood flow of adult male Sprague-Dawley rats, the lungs were perfused through the pulmonary artery cannula with a physiologic salt solution containing human serum albumin. The protective effect of ATP-MgCl(2) pretreatment with or without leukocytes was investigated. Capillary permeability (K(fc)), lung weight gain (LWG), lung wet weight/body weight ratio (LW/BW), lung lavage protein concentration (LPC) and pulmonary artery pressure (PAP) were measured. I-R produced a significant increase in K(fc), LWG, LW/BW, LPC, and PAP. The increases in these indices were significantly attenuated by pretreatment with ATP-MgCl(2) (1 x 10(-6)M) together with leukocytes (2.9 x 10(6)/ml in the perfusate) but not with ATP-MgCl(2) alone. Our data suggest that I-R-induced acute lung injury is not dependent on circulating leukocytes. Pretreatment with ATP-MgCl(2) plus leukocytes but not ATP-MgCl(2) alone had protective effects against I-R lung injury. Whether these findings occur in vivo could not be determined in this study. In our isolated lung red blood cell-free perfusate system, the protective effect of ATP-MgCl(2) requires the presence of leukocytes.