Chin-Pyng Wu

Stanniocalcin-1 ameliorates lipopolysaccharide-induced pulmonary oxidative stress, inflammation, and apoptosis in mice.

Stanniocalcin-1 (STC1) is an endogenous glycoprotein whose anti-inflammatory effects occur through induction of uncoupling proteins to reduce oxidative stress. In this study, we tested the hypothesis that exogenous recombinant human STC1 (rhSTC1) protects against lipopolysaccharide (LPS)-induced acute lung injury in mice. Anesthetized C57BL/6 mice underwent intratracheal spraying of LPS (20 µg/10 g body wt), and lung injury was assessed 24h later by analyzing pulmonary edema, bronchoalveolar lavage fluid, and lung histopathology. Lung inflammation, oxidative stress, and expression of STC1 and its downstream uncoupling protein 2 (UCP2) were analyzed at specific time points. Expression of UCP2 was suppressed initially but was subsequently upregulated after STC1 elevation in response to intratracheal administration of LPS. Intratracheal rhSTC1 treatment 1h before or after LPS spraying significantly attenuated pulmonary inflammation, oxidative stress, cell apoptosis, and acute lung injury. Pretreatment with STC1 short interfering RNA 48 h before LPS spraying inhibited the expression of STC1 and UCP2 and significantly increased the extent of lung injury. These findings suggest that STC1 is an endogenous stress protein that may counteract LPS-induced lung injury by inhibiting the inflammatory cascade and inducing antioxidant and antiapoptotic mechanisms. However, the potential clinical application of STC1 and the direct linkage between UCP2 and LPS-induced lung injury remain to be further investigated.

Hypercapnic acidosis attenuates reperfusion injury in isolated and perfused rat lungs.

Objective: Although ischemia–reperfusion injury is a major determinant of primary graft dysfunction after lung transplantation, an approach to extend preoperative lung preservation to postoperative protection has not yet been defined. The purpose of this study was to determine the protective effects of and the signal pathway regulated by hypercapnic acidosis in ischemia–reperfusion-induced lung injury. Design: Animal study. Setting: Animal care facility procedure room in a medical center. Subjects: Adult male Sprague-Dawley rats. Interventions: Lung injury was induced in a clinically relevant ex vivo animal model. Animals were divided into a control group (FICO2, 5%; n = 6), ischemia–reperfusion group (FICO2, 5%; n = 6), and hypercapnic acidosis (ischemia–reperfusion + hypercapnic acidosis) group (FICO2, 10%; n = 6). Measurements and Main Results: Ischemia–reperfusion caused significant increases in alveolar lavage and perfusate tumor necrosis factor-&agr;, inflammatory cell infiltration, lung tissue malondialdehyde, bronchoalveolar lavage fluid protein concentration and lactate dehydrogenase activity, lung weight gain, and infiltration coefficient. Ventilation with 10% CO2 significantly suppressed the inflammatory response and attenuated lung ischemia–reperfusion injury. Our results also showed that hypercapnic acidosis significantly inhibited the ischemia–reperfusion-induced phosphorylation and nuclear translocation of nuclear factor-&kgr;B. This was associated with elevation of inhibitor of nuclear factor-&kgr;B-&agr; level and reduced I&kgr;B kinase-&bgr; phosphorylation, suggesting a suppression of I&kgr;B kinase and thus I&kgr;B-&agr; activation. Conclusions: Hypercapnic acidosis may attenuate lung ischemia–reperfusion injury by suppressing the activation of the I&kgr;B kinase–nuclear factor-&kgr;B pathway.

Association of reduced tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1β but increased interleukin (IL)-10 expression with improved chest radiography in patients with pulmonary tuberculosis

ABSTRACT Mycobacterium tuberculosis infection is a major world health issue. The early identification of patients at risk for a poor response to anti-M. tuberculosis therapy would help elucidate the key players in the anti-M. tuberculosis response. The objective of the present study was to correlate the modulation of cytokine expression (interleukin-1 [IL-1], IL-6, IL-8, IL-10, IL-12, gamma interferon [IFN-γ], interferon-inducible protein [IP-10], and monocyte chemotactic protein 1 [MCP-1]) with the clinical response to 2 months of intensive therapy. From January to December 2007, 40 M. tuberculosis-infected patients and 40 healthy patients were recruited. After exclusion for diabetes, 32 patients and 36 controls were analyzed. The clinical responses of the M. tuberculosis-infected patients on the basis of the findings of chest radiography were compared to their plasma cytokine levels measured before and after 2 months of intensive anti-M. tuberculosis therapy and 6 months of therapy with human cytokine antibody arrays. Chest radiographs of 20 of 32 M. tuberculosis-infected patients showed improvement after 2 months of intensive therapy (early responders), while the M. tuberculosis infections in 12 of 32 of the patients resolved after a further 4 months (late responders). The levels of expression of TNF-α, MCP-1, IFN-γ, and IL-1β were decreased; and the level of IL-10 increased in early responders. After adjustment for age, gender, and the result of sputum culture for M. tuberculosis, significant differences in the levels of MCP-1 and IP-10 expression were observed between the early and the late responders after 2 months of intensive anti-M. tuberculosis therapy. Due to the interpatient variability in IP-10 levels, intrapatient monitoring of IP-10 levels may provide more insight into the M. tuberculosis responder status than comparison between patients. Plasma MCP-1 levels were normalized in patients who had resolved their M. tuberculosis infections. Further studies to evaluate the association of the modulation in MCP-1 levels with early and late responses are warranted.

Acute Respiratory Distress Syndrome After Zinc Chloride Inhalation: Survival After Extracorporeal Life Support and Corticosteroid Treatment

No standard protocol exists for the treatment of acute respiratory distress syndrome induced by inhalation of smoke from a smoke bomb. In this case, a 23-year-old man was exposed to smoke from a smoke grenade for approximately 10 to 15 minutes without protective breathing apparatus. Acute respiratory distress syndrome developed subsequently, complicated by bilateral pneumothorax and pneumomediastinum 48 hours after inhalation. Despite mechanical ventilation and bilateral tube thoracostomy, the patient was severely hypoxemic 4 days after hospitalization. His condition improved upon treatment with high-dose corticosteroids, an additional 500-mg dose of methylprednisolone, and the initiation of extracorporeal life support. Arterial oxygenation decreased gradually after abrupt tapering of the corticosteroid dose and discontinuation of the life support. On day 16 of hospitalization, the patient experienced progressive deterioration of arterial oxygenation despite the intensive treatment. The initial treatment regimen (ie, corticosteroids and extracorporeal life support) was resumed, and the patients arterial oxygenation improved. The patient survived.

Effects of Implementing Adaptive Support Ventilation in a Medical Intensive Care Unit

BACKGROUND: Adaptive support ventilation (ASV) facilitates ventilator liberation in postoperative patients in surgical intensive care units (ICU). Whether ASV has similar benefits in patients with acute respiratory failure is unclear. METHODS: We conducted a pilot study in a medical ICU that manages approximately 600 mechanically ventilated patients a year. The ICU has one respiratory therapist who manages ventilators twice during the day shift (8:00 am to 5:00 pm). No on-site respiratory therapist was present at night. We prospectively enrolled 79 patients mechanically ventilated for ≥ 24 hours on pressure support of ≥ 15 cm H2O, with or without synchronized intermittent mandatory ventilation, FIO2 ≤ 50%, and PEEP ≤ 8 cm H2O. We switched the ventilation mode to ASV starting at a “%MinVol” setting of 80–100%. We defined spontaneous breathing trial (SBT) readiness as a frequency/tidal-volume ratio of < 105 (breaths/min)/L on pressure support of ≤ 8 cm H2O and PEEP of ≤ 5 cm H2O for at least 2 h, and all spontaneous breaths. The T-piece SBT was considered successful if the frequency/tidal-volume ratio remained below 105 (breaths/min)/L for 30 min, and we extubated after successful SBT. The control group consisted of 70 patients managed with conventional ventilation modes and a ventilator protocol during a 6-month period immediately before the ASV study period. RESULTS: Extubation was attempted in 73% of the patients in the ASV group, and 80% of the patients in the non-ASV group. The re-intubation rates in the ASV and non-ASV groups were 5% and 7%, respectively. In the ASV group, 20% of the patients achieved extubation readiness within 1 day, compared to 4% in the non-ASV group (P = <.001). The median time from the enrollment to extubation readiness was 1 day for the ASV group and 3 days for the non-ASV group (P = .055). Patients switched to ASV were more likely to be liberated from mechanical ventilation at 3 weeks (P = .04). Multiple logistic regression analysis showed that, of the independent factors in the model, only ASV was associated with shorter time to extubation readiness (P = .048 via likelihood ratio test). CONCLUSIONS: Extubation readiness may not be recognized in a timely manner in at least 15% of patients recovering from respiratory failure. ASV helps to identify these patients and may improve their weaning outcomes.

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%).

Effect of hyperbaric oxygen on endotoxin-induced lung injury in rats

Oxygen therapy remains the main component of the ventilation strategy for treatment of patients with acute lung injury. Hyperbaric oxygen therapy (HBO2) is the intermittent administration of 100% oxygen at pressure greater than sea level and has been applied widely to alleviate a variety of hypoxia-related tissue injuries. The purpose of this study was to evaluate the effect of hyperbaric oxygen on acute lung injury induced by intratracheal spraying of lipopolysaccharide (LPS) in rats. Male Sprague-Dawley rats underwent implantation of a carotid artery catheter under general anesthesia. Aerosolized LPS was delivered twice into the lungs via intratracheal puncture. Animals were either breathing room air (n = 27) or subjected to hyperbaric oxygen (HBO2) exposure (n = 27) 1 h after LPS spraying. Acute lung injury was evaluated 5 h and 24 h later. Compared with the control group, intratracheal spraying of LPS caused profound hypoxemia, greater wet/dry weight ratio (W/D) of the lung (5.67 ± 0.22 vs. 4.98 ± 0.19), and higher protein concentration (1706 ± 168 vs. 200 ± 90 mg/L) and LDH activity (129 ± 30 vs. 46 ± 15, mAbs/min) in bronchoalveolar lavage (BAL) fluid. Intratracheal spraying of LPS also caused significant WBC sequestration in the lung tissue. HBO2 treatment significantly reverted hypoxemia, reduced lung injury measures evaluated at 5 and 24 h, and enhanced 24-h animal survival rate (χ2 = 5.08, P = 0.024). The malondialdehyde (MDA) concentrations in lung tissue and serum were both increased after LPS spraying. Neither single HBO2 therapy nor five sequential daily treatments enhanced MDA production in lung tissue or serum. Our results suggested that hyperbaric oxygen might reduce acute lung injury caused by intratracheal spraying of LPS in rats. This treatment modality is not associated with enhancement of oxidative stress to the lung.

Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia-reperfusion injury in rat lung

1. An intervention to reduce ischaemia-reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia-reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia-reperfusion-associated lung vascular injury.2. The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 h of cold ischaemia followed by 1 h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dexx3, (5) UW+PGE1x3, (6) UW+Bt2-cAMPx3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs.3. The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs.4. Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia-reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia-reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

Effect of body positions on hemodynamics and gas exchange in anesthetized pigs shortly after pneumonectomy.

Positional changes are thought to affect hemodynamics, respiratory mechanics, and gas exchange after pneumonectomy. The objective of this study was to compare hemodynamic and respiratory parameters and gas exchange in different positions before and after pneumonectomy. Twenty pigs were anesthetized and mechanically ventilated. Seven received right-side pneumonectomy, seven received left-side pneumonectomy, and six were anesthetized but did not receive surgery and served as controls. Hemodynamic and respiratory parameters and blood gas values were measured in different positions (supine and right and left lateral decubitus). Minute mechanical ventilation was controlled throughout. Pneumonectomy resulted in significant reductions in MAP, accompanied by significant decreases in cardiac index, stroke volume index, global ejection fraction, and global end-diastolic volume index. Mean pulmonary arterial pressure and pulmonary vascular resistance index increased. PaCO2, airway resistance, and peak airway pressure increased, whereas PaO2 and lung compliance decreased. Hemodynamic and respiratory parameters and gas exchange were also significantly affected by changes in position with pneumonectomy. Mean arterial pressure, cardiac index, stroke volume index, global ejection fraction, and global end-diastolic volume index were significantly lower in the supine than in the right or left lateral decubitus position. PaO2 was significantly higher in a lateral position, with the remaining lung uppermost. Our findings suggest that avoiding the supine positioning after pneumonectomy may facilitate improvements in hemodynamics and a decreased risk of hypoxemia. The optimal position for gas exchange after pneumonectomy is a lateral position, with the remaining lung in the uppermost position.

Hyperbaric oxygen attenuates cell growth in skin fibroblasts cultured in a high-glucose medium

Hyperglycemia and hypoxia synergistically retard diabetic wound healing. We investigated the direct effect of hyperbaric and normobaric hyperoxia on skin fibroblasts cultured in a high‐glucose medium. Detroit 551 human dermal fibroblasts cultured in Dulbeccos modified Eagles medium containing d‐glucose had reduced cell survival compared with cells grown in normal glucose medium; survival was 27.5±3.8% lower in 25 mM glucose and 30.6±3.7% lower in 50 mM glucose. Cell survival decreased because of inhibition of cell proliferation and enhanced cell death. Daily hyperbaric oxygen therapy at 2.5 atmosphere absolute for 90 minutes on 3 consecutive days reduced cell proliferation and increased cell death in normal cultured fibroblasts. Hyperbaric oxygen therapy and high‐glucose medium had a synergistic effect and reduced survival by 37.6±4.4% (25 mM glucose) and 39.6±5.1% (50 mM glucose). The effects of hyperbaric oxygen and high‐glucose medium were associated with overproduction of reactive oxygen species. Our results suggest that direct exposure of skin fibroblasts to hyperbaric oxygen affects cell growth and superimposes the toxic effect of high glucose. This cytotoxicity may be related to the production of reactive oxygen species in the fibroblasts.