Involvement of Akt and endothelial nitric oxide synthase in ventilation-induced neutrophil infiltration: a prospective, controlled animal experiment.

INTRODUCTION: Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human IL-8, and neutrophil infiltration. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between a large tidal volume and hyperoxia are unclear. We hypothesized that large tidal volume ventilation using hyperoxia would increase MIP-2 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway and the endothelial nitric oxide synthase (eNOS) pathway. METHODS: C57BL/6 mice were exposed to large tidal volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 1-5 hours. RESULTS: Large tidal volume ventilation using hyperoxia induced neutrophil migration into the lung, MIP-2 production, and Akt and eNOS activation in a time-dependent manner. Both the large tidal volume ventilation of Akt mutant mice and the pharmacological inhibition of Akt with LY294002 attenuated neutrophil sequestration, MIP-2 protein production, and Akt and eNOS activation. CONCLUSION: We conclude that hyperoxia increased large tidal volume-induced MIP-2 production and neutrophil influx through activation of the Akt and eNOS pathways.

Hyperoxia increases ventilator-induced lung injury via mitogen-activated protein kinases: a prospective, controlled animal experiment.

INTRODUCTION: Large-tidal volume (VT) mechanical ventilation and hyperoxia used in patients with acute respiratory distress syndrome can damage pulmonary epithelial cells through lung inflammation and apoptotic cell death. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between large VT and hyperoxia are unclear. We hypothesized that the addition of hyperoxia to large-VT ventilation would increase neutrophil infiltration by upregulation of the cytokine macrophage inflammatory protein-2 (MIP-2) and would increase apoptosis via the mitogen-activated protein kinase pathways. METHODS: C57BL/6 mice were exposed to high-VT (30 ml/kg) mechanical ventilation with room air or hyperoxia for one to five hours. RESULTS: The addition of hyperoxia to high-VT ventilation augmented lung injury, as demonstrated by increased apoptotic cell death, neutrophil migration into the lung, MIP-2 production, MIP-2 mRNA expression, increased DNA binding activity of activator protein-1, increased microvascular permeability, and c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activation. Hyperoxia-induced augmentation of high-VT-induced lung injury was attenuated in JNK-deficient mice and in mice with pharmacologic inhibition of ERK activity by PD98059. However, only JNK-deficient mice, and not mice with ERK activity inhibition by PD98059, were protected from high-VT-induced lung injury without hyperoxia. CONCLUSION: We conclude that hyperoxia increased high-VT-induced cytokine production, neutrophil influx, and apoptotic cell death through activation of the JNK and ERK1/2 pathways.

A comparison of the long-term outcome and effects of surgery or continuous positive airway pressure on patients with obstructive sleep apnea syndrome.

OBJECTIVES: To compare the long-term (3-year) outcome and effects of continuous positive airway pressure (CPAP) and extended uvulopalatoplasty (EUPF) treatment on patients with obstructive sleep apnea syndrome. METHODS: Eighty-four patients who received CPAP titration and bought a CPAP machine to use from March 2000 to October 2001 were included as the CPAP group. Another 55 patients who underwent EUPF surgery were included as the EUPF group. Overnight polysomnography was performed 6 months and 3 years after CPAP titration or EUPF. The disease-specific questionnaire-Snore Outcome Survey (SOS), Epworth Sleepiness Scale (ESS), and the generic health questionnaire-MOSF-36 were administered at the 6-month and 3-year follow-up examinations. RESULTS: The age, body mass index, respiratory disturbance index, and ESS before treatment were higher in the CPAP group. The snore index was higher in the surgery group. Fifty-four patients (64.3%) in CPAP group continued treatment for 6 months; the success rate for EUPF at 6 months was 82%. The polysomnographic variables improved significantly in both groups. Improvements in the SOS and ESS scores were better in surgery group than the CPAP group. The subscales of SF-36 in surgery group were more than those in CPAP group. CONCLUSIONS: EUPF had a better effect on snoring than CPAP 6 months after treatment in patients with obstructive sleep apnea syndrome (OSAS). This effect had gradually declined at the 3-year follow-up examination. Improvement in the quality of life of OSAS patients receiving EUPF is equal to those receiving CPAP treatment.

Weekly short infusion of taxotere at a 4 week cycle in Chinese patients with advanced NSCLC who have failed or relapsed after the frontline platinum-based non-taxane chemotherapy--a Phase II trial.

BACKGROUND: This Phase II study was conducted to evaluate the efficacy and toxicity of weekly docetaxel at a 4 week cycle in second-line therapy for patients with advanced non-small cell lung cancer (NSCLC) who failed to respond or relapsed after the frontline platinum-based, non-taxane regimen. METHODS: Patients with histologically confirmed and progressive NSCLC after one platinum-based, non-taxane regimen were eligible for this study. Performance status of 0-2 and adequate organ function were required. Patients were treated with docetaxel 40 mg/m(2)/week for three consecutive weeks then following 1 week of rest. Cycles were repeated every 4 weeks for a maximum total of six cycles. Docetaxel was administered intravenously for 30 min with dexamethasone premedication. RESULTS: Fifty-three patients were eligible for this study. Hematologic toxicity was very mild and with the major toxicity of anemia. Non-hematologic toxicities were modest, Grades 3-4 mucositis, diarrhea and peripheral neuropathy occurred in 6-13% of patients and caused dose modifications. Fatigue (48%) was common but not severe with only 6% of Grades 3-4 toxicity. The overall response rate (ORR) was 13% [95% confidence interval (CI), 3.9-23%]. The median survival time (MST) for all patients was 25.0 weeks (95% CI, 12.7-37.3), and the 1 year survival was 31% (95% CI, 17-58%). For patients with PS 0-1, MST was 29.7 weeks and 1 year survival was 36%. CONCLUSIONS: Weekly docetaxel appeared to be well tolerated as second-line therapy for patients with NSCLC. The efficacy for this regimen was comparable with the standard 3 week schedule but hematologic toxicity was markedly reduced. A schedule of three consecutive weeks, with a 1 week break, may diminish the frequency of fatigue and diarrhea when compared with a schedule of six consecutive weeks.

Invasive pulmonary aspergillosis and pulmonary cryptococcosis really coexist in immunocompromised host.

Fungal infections develop slowly in immunocompetent patients and rarely a severe disease, however, they progress rapidly and usually prove fatal in immunocompromised patients. Early diagnosis and treatment of fungal infections is essential to survival of immunocompromised patients. We report a 33-year-old woman with systemic lupus erythematosus undergoing immunotherapy infected with combined invasive pulmonary aspergillosis and pulmonary cryptococcosis diagnosed by video-assisted thoracic surgery lung biopsy and she was successfully treated as a result of early diagnosis and treatment.

Dose-finding and phase 2 study of weekly paclitaxel (taxol) and cisplatin combination in treating Chinese patients with advanced nonsmall cell lung cancer.

OBJECTIVES: The aim of the present study is to evaluate the efficacy and toxicity of weekly paclitaxel combined with cisplatin as first-line chemotherapy in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) and to identify the optimal dose of weekly paclitaxel to be administered safely and effectively. METHODS: Chemonaive patients with NSCLC, stage 3B with malignant pleural effusion, or stage 4 were enrolled in this study. In the dose-finding study, patients took paclitaxel once weekly at an initial dose of 50 mg/m2 and 3 weeks followed by cisplatin on day 15 at a fixed dose of 80 mg/m2. The escalating dose for paclitaxel was 10mg/m2 for each level. In the phase 2 study, patients received paclitaxel at maximum tolerated dose (MTD). RESULTS: The MTD for paclitaxel was 60 mg/m2. Of the 47 eligible patients, 7 patients had a complete response and 15 achieved a partial response. The overall response was 46.8% (95% CI, 32.0% to 61.6%). The median survival was 16 months (95% CI, 13.4 to 18.6 months). Twenty-four patients (51.1%) completed 6 cycles of treatment. With regard to hematological toxicity, although grade 3/4 neutropenia was observed in 5 patients (10.6%), there was no febrile neutropenia. The major nonhematological toxicity was asthenia, which was observed in all patients (17 patients grade 1/2 and 30 patients with grade 3/4). CONCLUSIONS: Weekly paclitaxel combined with cisplatin on day 15 is a safe and effective regimen as a first-line chemotherapy in NSCLC. The MTD for this regimen was 60 mg/m.

Ventilation-induced neutrophil infiltration and apoptosis depend on apoptosis signal-regulated kinase 1 pathway.

OBJECTIVE: Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein (MIP)-2, a functional equivalent of human interleukin-8, neutrophil infiltration, and apoptosis. The mechanisms regulating ventilation-induced cytokine production and lung cell death are unclear. Based on our previous in vitro and in vivo models of lung cell stretch, we hypothesized that high tidal volume ventilation-induced MIP-2 production, neutrophil infiltration, and apoptosis are dependent on the activation of apoptosis signal-regulated kinase 1 (ASK1), the upstream activator of c-Jun N-terminal kinase (JNK). DESIGN: : Prospective, controlled animal experiment. SETTING: University research laboratory. SUBJECTS: Male C57BL/6 mice, weighting 20-25 g. INTERVENTIONS: C57BL/6 mice were exposed to high tidal volume (30 mL/kg) or low tidal volume (6 mL/kg) mechanical ventilation for 15 mins to 5 hrs. MEASUREMENTS AND MAIN RESULTS: High tidal volume ventilation induced MIP-2 messenger RNA expression, MIP-2 protein production, neutrophil migration into the lung, airway epithelial cell apoptosis, and activation of ASK1, JNK, and activator protein (AP)-1 DNA binding in a dose-dependent and time-dependent manner. ASK1 inhibition with thioredoxin attenuated high tidal volume ventilation-induced MIP-2 messenger RNA expression, MIP-2 protein production, neutrophil migration into the lung, airway epithelial cell apoptosis, activation of JNK, and AP-1 DNA binding. CONCLUSIONS: Our data showed that high tidal volume ventilation-induced MIP-2 production, neutrophil sequestration, and apoptotic cell death were dependent, in part, on activation of the ASK1/JNK/AP-1 pathway.

Outcome analysis of patients requiring mechanical ventilation with severe community-acquired pneumonia and identified bacterial pathogens.

BACKGROUND: Severe community-acquired pneumonia (CAP) is associated with high mortality. The choice of antibiotics should be guided by the distribution of bacterial pathogens. The purpose of this study was to analyze the causative bacteria and outcomes of patients with severe CAP in a medical intensive care unit (MICU) in Taiwan. The results may provide a basis of guidance for future empirical antibiotic treatments. METHODS: We enrolled patients with severe CAP who were intubated and who required mechanical ventilation in an MICU in 2001. Only patients with identified bacterial pathogens were included. The bacterial distribution was determined, while differences in age, acute physiology and chronic health evaluation (APACHE) II scores, and initial PaO2/FiO2 ratio between surviving and expired patients were compared. RESULTS: Fifty-nine patients were enrolled and 75 isolates were obtained. Klebsiella pneumoniae was the most common bacteria (21.3%), followed by Pseudomonas aeruginosa and Acinetobacter baumannii. Staphylococcus aureus (8%) was the most-commonly isolated gram-positive organism, and half of its isolates were oxacillin-resistant (ORSA). The overall mortality was 55.9%. Multiple logistic regression analysis revealed that survivors had a significantly younger age and lower APACHE II scores. CONCLUSIONS: Gram-negative bacilli were the most-common causative pathogens among patients with severe CAP requiring mechanical ventilation. Antipseudomonal antibiotics or a carbapenem should be considered to cover Pseudomonas species, extended-spectrum beta-lactamase-producing strains, and Acinetobacter species. If the isolated bacteria are gram-positive, care should be taken to cover the possibility of ORSA. Old age and higher APACHE II scores were associated with higher mortality.