Inducible cyclooxygenase expression mediating hypoxia/reoxygenation-induced pulmonary vasoconstriction is attenuated by a cyclooxygenase inhibitor in rats.

OBJECTIVE: Hypoxic pulmonary vasoconstriction (HPV) is a well known phenomenon to temporarily offset a ventilation-perfusion mismatch. Sustained HPV may lead to pulmonary hypertension. In this protocol, we studied the relationships between the HPV response and inducible cyclooxygenase II (COX II) activation after hypoxia-reoxygenation (H-R) challenge in an isolated perfused lung model. METHODS: An in situ isolated perfused rat lung model underwent inaction of hypoxia by ventilation with 5% CO(2)-95% N(2) for 10 minutes instead of 5% CO(2)-95% air; they were then reoxygenated with 5% CO(2)-95% air. We measured pulmonary arterial pressure (PAP) changes before, during, and after H-R challenge. We also estimated changes in blood concentrations of hydroxyl radicals, nitric oxide (NO) and thromboxane B(2) (TxB(2)) before and after H-R as well as mRNA expressions of COX II in lung tissue thereafter. A COX II inhibitor, celecoxib (10 mg/kg), was administered between 2 consecutive challenges. RESULTS: Hypoxia induced pulmonary vasoconstriction by increasing PAP (4.1 ± 0.8 mm Hg). Consecutive hypoxic challenges did not show tachyphylaxis (P > .05). H-R of lung tissues induced significant increases in blood concentrations of hydroxyl radicals (48.5 ± 7.6 vs 75.8 ± 11.5 mmol/L; P < .01), NO (54.3 ± 12.3 vs 77.7 ± 15.7 pmol; P < .05), and TxB(2) (42.3 ± 6.9 vs 58.7 ± 8.6 pg/mL; P < .05). Lung tissue H-R also significantly increased COX II mRNA expression compared with sham tissues (1 ± 0 vs 4.0 ± 2.8; P < .001). The COX II inhibitor celecoxib significantly attenuated HPV responses (P < .05) and attenuated the elevated blood concentrations of TxB(2) (P < .05), hydroxyl radicals (P < .01), nitric oxide (P < .05), and COX II mRNA expression (P < .05) after H-R challenge. CONCLUSIONS: Lung tissue H-R induced significant increases blood concentrations of inflammatory mediators and tissue mRNA expression of COX related to elevation of HPV responses. COX II inhibitor celecoxib attenuated the HPV responses by reducing TxB(2) release.

The protective effect of curcumin on ischemia-reperfusion-induced liver injury.

OBJECTIVE: Reperfusion of the ischemic liver results in the generation of oxidative and nitrosative stresses and reaction product of peroxynitrite, which induce rapid cytotoxicity and liver injury. In this study we demonstrated that curcumin, an antioxidant, attenuated ischemia/reperfusion (I/R)-induced liver injury. MATERIALS AND METHODS: Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 30 minutes. Thereafter, flow was restored and the liver was reperfused for 80 minutes. Blood samples collected prior to ischemia and after reperfusion were analyzed for methyl guanidine (MG), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and adenosphate triphosphate (ATP). Blood levels of serum glutamic oxaloacetic transaminase (sGOT), serum glutamate pyruvate transaminase (sGPT), and lactic dehydrogenase (LDH), which served as indexes of liver injury, were measured. RESULTS: The protocol resulted in elevation of blood NO (P < .001), TNF-α (P < .001), and MG (P < .001). sGOT, sGPT, and LDH were elevated significantly (P < .001), whereas ATP was significantly diminished (P < .001). Pretreatment with curcumin (25 mg/kg) significantly attenuated the reperfusion liver injury, while the ATP content reversed. In addition, MG, TNF-α, and NO release were attenuated. CONCLUSIONS: These results indicated that curcumin exerted potent anti-inflammatory effects in I/R-induced liver injury due to its antioxidant effects.

Cyclosporine, an immunosuppressant, attenuates phorbol-induced lung injury in rats.

OBJECTIVE: White cell activation in the lung plays a critical role to induce lung injury and lymphocytes in the thoracic duct system may also participate. We evaluated the effect of cyclosporine on phorbol myristate acetate (PMA)-induced lung injury. MATERIALS AND METHODS: We used an in situ isolated, blood perfused rat lung model to measure pulmonary arterial pressure (PAP) and lung weight gain (LWG; g) for 50 minutes after a bolus injection of PMA (0.05 microg/mL). Oxygen radical release was estimated by an LKB 1251 luminometer and by nitric oxide (NO) release as measured by an ENO-20 NO analyzer. RESULTS: In the group exposed to PMA alone, the mean PAP increased from 16.53 +/- 1.28 to 43.33 +/- 3.40 mm Hg (P < .001), and lung weight increased by 4.35 +/- 0.67 g during the 50-minute perfusion after PMA challenge (P < .001). In vitro measurement showed that PMA induced a significant increase in oxygen radical release (P < .001). PMA attenuated NO release (P < .001) into the perfusion system. Pretreatment with cyclosporine (3 mg/kg) for 3 days prevented the increases in both PAP (P < .01) and LWG (P < .001). NO release was maintained in cyclosporine-pretreated rats. Cyclosporine also showed dose-dependent attenuation of oxygen radical release by PMA-activated white blood cells. CONCLUSION: The mechanisms responsible for the protective effect of cyclosporine on the lung injury induced by phorbol may be related to an attenuation of oxygen radical production with maintenance of NO release.

Apoptosis-dependent and -independent mechanisms mediate the phagocytic recognition/clearance of the HL60-A1 transfectants with prolonged survival.

OBJECTIVE: The phagocytic recognition and clearance of the recruited inflammatory cells with prolonged survival play a pivotal role in relieving tissue inflammation and maintaining tissue homeostasis. Transgenic mice expressing Bcl-2 in mature neutrophils demonstrated that Bcl-2 attenuated neutrophil apoptosis, while the homeostasis of the neutrophil population was essentially unaffected. This result suggests that clearance of neutrophils with prolonged survival operates independently from apoptosis. Owing to the constitutive and inducible expression of Bcl-2 homologue, A1 in human neutrophils and the intolerance of preparation for the isolated human neutrophils with prolonged survival, the human promyelocytic HL60-A1 transfectants were established to study the mechanism of phagocytic recognition/clearance of the cells with prolonged survival. MATERIALS AND METHODS: The non-apoptotic cells with prolonged survival were enriched by serum withdrawal for five days and negatively isolated by annexin V-binding beads. Then, the cells were labeled with a fluorogenic marker. Monocyte-derived macrophages (MDM) were co-cultured to perform the phagocytosis assay, and flow cytometry was employed to determine the phagocytic index. RESULTS: In the serum-free condition, the phagocytic index of HL60-A1 transfectants was little different from that of the HL60-EGFP control, despite showing a significantly lower degree of apoptosis. While the phagocytic index of HL60-EGFP control was significantly correlated with the degree of apoptosis, the index of the HL60-A1 transfectants was less relevant to it. The phagocytic index for the annexin V-positive cells did not distinguish the two cell types. However, the phagocytic index for the annexin V-negative cells from the HL60-A1 transfectants was increased with age in days. Preincubation of MDM with the scavenger receptor inhibitor, Oxi-LDL, and the inhibitory antibodies against alphavbeta3, CD14 and CD36 surface molecules could attenuate the phagocytic recognition of the annexin V-positive HL60 cells but not the annexin V-negative A1 transfectants with prolonged survival. CONCLUSIONS: This study thus suggests that a mechanism unrelated to apoptosis exists, which mediates the phagocytic clearance of the non-apoptotic cells with prolonged survival and may be associated with A1 function in the myeloid cells.

Involvement of nuclear factor-kappaB in lipoteichoic acid-induced cyclooxygenase-2 expression in RAW 264.7 macrophages.

We have investigated the role of protein kinase C (PKC) and nuclear factor-kappaB (NF-kappaB) in cyclooxygenase-2 (COX-2) expression caused by Staphylococcus aureus lipoteichoic acid in RAW 264.7 macrophages. A phosphatidylcholine-phospholipase C (PC-PLC) inhibitor (D-609) and a phosphatidylinositol-phospholipase C (PI-PLC) inhibitor (U-73122) attenuated lipoteichoic acid-induced COX-2 expression, while a phosphatidate phosphohydrolase inhibitor (propranolol) had no effect. Two PKC inhibitors (Go 6976 and Ro 31-8220) and the NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), also attenuated lipoteichoic acid-induced COX-2 expression. Lipoteichoic acid resulted in a decrease in PKC activity in the cytosol and an increase in PKC activity in membranes. The lipoteichoic acid-induced translocation of p65 NF-kappaB from the cytosol to the nucleus was inhibited by D-609, U-73122, Go 6976, Ro 31-8220, and PDTC, but not by propranolol. The results suggested that lipoteichoic acid might have activated PC-PLC and PI-PLC to induce PKC activation, which in turn initiated NF-kappaB activation, and finally induced COX-2 expression in RAW 264.7 macrophages.

Relationship between six-minute walking test and pulmonary function and ventilatory drive in patients with airflow limitation.

BACKGROUND: We studied the correlation between exercise tolerance and pulmonary function, arterial blood gases, and ventilatory drive in patients with airflow limitation (AFL). METHODS: Forty-one patients (36 men, 5 women, mean age 63.6 +/- 10.3 years) with forced expiratory volume in one second (FEV1) < 75% and FEV1/forced vital capacity (FVC) < 75% were enrolled. All patients were clinically stable with no impairment of the lower extremities. On the first day of the study, pulmonary function test (PF), including FVC, FEV1, diffusion capacity (DLCO), and residual volume (RV)/total lung capacity (TLC) was measured by plethysmography. On the next day, ventilatory drive P0.1 were measured before drawing blood gases. Then, a 6-minute walking test with pulse-oxymetry and end tidal CO2 monitoring was performed. Ventilation efficiency (O2SATp & ETCO2) was recorded every 6 seconds during exercise. RESULTS: The walking distance (WD) was significantly correlated to PF: FVC%, FEV1%, DLCO%, and RV/TLC. There was also a significant correlation between resting arterial blood gases (PaO2, PaCO2, SatO2) and PF (FVC%, FEV1%, DLCO% and RV/TLC). The SatO2 at the end of exercise was highly correlated to PF (FVC%, FEV1%, DLCO% and RV/TLC). Gas exchange parameters: PaO2, PaCO2, O2SATa, O2SATp at rest, and O2SATp at the end of exercise were also significantly related to WD. CONCLUSION: The magnitude of exercise intolerance in patients with AFL was not only significantly correlated to the impairment of pulmonary function, but also closely related to gas exchange during exercise. Therefore, limitation of ventilation could be identified earlier using an exercise test.

The effect of incentive spirometry on chest expansion and breathing work in patients with chronic obstructive airway diseases: comparison of two methods.

BACKGROUND: Chronic obstructive airway diseases (COAD), characterized by mucus hypersecretion, lead to exercise intolerance. Incentive spirometry has been used to prevent postoperative pulmonary atelectasis. METHODS: To compare the efficacy of two incentive spirometers, Coach (volume-oriented) and Triflo (flow-oriented), in the work of breathing in COAD patients, 22 patients were randomized in this study: 12 patients (Triflo-II group) initially used Triflo-II for 10 minutes and then Coach for the same period. In contrast, the Coach group, including 10 patients, started with Coach followed by Triflo-II. After receiving incentive spirometry, lung expansion and work of breathing were assessed. RESULTS: Patients in the Coach group significantly increased chest wall expansion (p = 0.041), as compared with patients using Triflo-II. Similarly, there was also a significantly increased abdominal wall expansion in the Coach group (p = 0.0056), compared with that in the Triflo-II group. The need of accessory muscle assistance for breathing in the Coach group was significantly less than in the Triflo-II group (p = 0.047). It was easier for patients in the Coach group to start a breath (p = 0.0058) than for those in the Triflo-II group. For the entire group, 17 patients (77.3%) preferred Coach to assist their breathing, and only 4 patients (18.2%) favored Triflo-II. CONCLUSION: COAD patients achieved a larger expansion of the chest and abdomen with a Coach device. Our data provide a good rationale for an outcome study on the use of incentive spirometer in COAD patients.

Chest physiotherapy does not exacerbate gastroesophageal reflux in patients with chronic bronchitis and bronchiectasis.

BACKGROUND: Chest physiotherapy is beneficial to patients with mucus hypersecretion. However, it is not risk-free. Chest physiotherapy may affect gastrointestinal motility and the competence of the gastroesophageal sphincter during the procedure. Our study was aimed to investigate whether gastroesophageal reflux is exacerbated or induced by chest physiotherapy. MATERIALS AND METHODS: Thirty-two adult patients with chronic bronchitis or bronchiectasis received chest physiotherapy. An esophageal pH meter was placed 5 cm above the gastroesophageal junction and monitored the reflux episodes from 8 AM on the first day to 12 noon on the second day. Physiotherapy was performed with the patient in three different positions on the second day for one hour. RESULTS: Thirteen patients were found to have gastroesophageal reflux disease. For the study group as a whole, neither the frequency nor the duration of having a pH < 4 during the physiotherapy was significantly different from the mean hourly frequency and mean hourly duration recorded on the first day or from those values recorded at a corresponding time on the first day. As for the patients with gastroesophageal reflux disease, the frequency and total duration of gastroesophageal reflux during physiotherapy were not significantly different from the mean hourly frequency and the mean hourly duration or from the values recorded at the corresponding time on the first day. There was no significant difference in the gastroesophageal reflux frequency or the duration in different body positions. CONCLUSION: Chest physiotherapy including postural drainage, percussion and forced expiration techniques in different positions did not induce or increase the incidence of gastroesophageal reflux in patients with chronic bronchitis and bronchiectasis.

Effect of nebulized fenoterol on spirometry, dyspnea sensation changes during exercise in patients with chronic obstructive pulmonary disease.

Airflow limitation impairs exercise capacity in patients with chronic obstructive pulmonary disease (COPD). Bronchodilators have been shown to increase exercise tolerance in patients with COPD by mechanisms yet unclarified. We studied the effect of nebulized fenoterol (0.5 mg/ml) on the 6-minute walking test (WT) 60 mins after a control WT using a nebulized saline control in 16 patients with moderate to severe COPD. Before and immediately after each WT, the FEV1, FVC, O2, Saturation and dyspnea score (Borg breathlessness score,[BS]) were measured. Fenoterol had no significant effect on pre-exercise spirometry in our patients but maintained a significantly higher level of FEV1 (0.9 +/- 0.1L, p < 0.0001) and FVC (2.0 +/- 0.2L, p < 0.01) immediately after exercise than that after saline control nebulization (0.7 +/- 0.1L, 1.8 +/- 0.2L, respectively). Fenoterol significantly (p < 0.01) increased walking distance (WD) from 201.3 +/- 22.2m to 238.9 +/- 22.2m, but no difference was found in BS and oxygen saturation. The decline in FEV1 following the WT was shown to have an inverse relationship (r = - 0.74, p < 0.002) with the WD improvement (delta WD). Those who walked farther after fenoterol inhalation felt less dyspnea after exercise, also with an inverse correlation (r = -0.61, p < 0.02). These results suggest that fenoterol may improve exercise capacity by preventing airflow deterioration during exercise in patients with COPD. We also recommend the 6-minute walking test in the routine clinical assessment of COPD patients to evaluate the symptomatic benefit offered by betamimetic bronchodilators.

[Long-term mechanical ventilation survey].

Although home mechanical ventilation is common in western countries, it is still extremely rare in Taiwan. The objectives of this study are (1) to review retrospectively the types of disorders and outcomes of these patients requiring prolonged mechanical ventilation (MV), and (2) to survey the home status of twelve patients on home mechanical ventilation. From January 1990 to April 1992, one hundred fifteen patients receiving prolonged MV ( > or = 30 days & > or = 8-10 hrs/day) were studied in the medical intensive care unit at Chang Gung Memorial Hospital. Eighty-two patients (71.3%) for whom long-term MV were thought to be beneficial were divided into three groups by disorder: (1)primary pulmonary disorder (N = 55, 67.07%) (2) neuromuscular disorder (N = 18, 21.95%), (3) brain stem disorder (N = 9, 10.98%). The outcomes of these eighty-two patients were as follows: expired, 37 (45.12%), completely weaned, 21 (25.61%), unweanable 24, including 12 (14.63%) hospitalized and 12 (14.63%) discharged home. The three outcomes of prolonged MV were significantly associated with the three types of disorder (P = 0.0035). Among these three disorders, duration of MV were longest in the neuromuscular group, whatever the outcome. There was significant difference in the duration of MV for the different outcomes of group I & group III. The mean duration at home for the twelve home MV patients (5 male and 7 female, mean age +/- SD = 46.08 +/- 20.83 years old) was 9.93 +/- 8.11 month, with the longest being 21.5 months. Four expired within two months of discharge to home, two patients had to be readmitted once (one C2-C5 spinal cord injury patient for pneumonia, and the other for brain stem deterioration). When comparing hospital stay, four patients improved in the maximal free time (the mean improvement, 5.75 +/- 3.11 hours/day), seven remained unchanged, while one regressed.(ABSTRACT TRUNCATED AT 250 WORDS)