Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia o... more Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in >90% FIO2 for
Pleomorphic carcinoma is an extremely rare histological type of lung malignancy. Although it carr... more Pleomorphic carcinoma is an extremely rare histological type of lung malignancy. Although it carries an aggressive clinical course, intracardiac extension has never been reported before. We describe a 53-year-old lady presented to our emergency department with progressive shortness of breath and intermittent fever for six weeks. After detailed work-up, a lung tumor with intracardiac extension via pulmonary vein to the left atrium was disclosed. Pathologic examination of a computerized tomography-guided lung biopsy showed pleomorphic carcinoma. The patient underwent wide excision of the left atrial tumor and subsequent right pneumonectomy smoothly. Both the left atrial and lung tumors showed the same histologic picture of pleomorphic carcinoma. However, brain metastasis was disclosed three months after operation. The patient eventually died of severe sepsis six months later.
Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer p... more Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer patients in Taiwan. We hypothesized that early integration of radiotherapy during TKI treatment would decrease the chance of drug resistance and prolong progression-free survival (PFS). This study included 25 patients with stage IIIb or IV non-squamous cell, non-small cell lung cancer (NSqCLC) who responded to upfront TKI treatment. Multi-target radiotherapy was administered during the TKI treatment course. Tomotherapy comprising a hypofractionated schedule with a dose of 40-50 Gy in 16-20 fractions was used for individual metastatic lesions. The patients' median follow-up duration was 30 months (range, 9-62 months). Of the 23 patients who had stage IV disease, 9 had oligometastases (≤5 gross target volumes) and 14 were in the more advanced stages of the disease. Twelve patients received more than 1 cycle of radiotherapy (median, 3; range, 2-6) with TKI being the only systemic treatme...
Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia o... more Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challeng...
Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal inj... more Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals;...
Ischemia/reperfusion (I/R) of the rat liver can induce liver injury through mechanisms involving ... more Ischemia/reperfusion (I/R) of the rat liver can induce liver injury through mechanisms involving oxidative and nitrosative stresses. In this study we examined the effects of antioxidants Lycium barbarum (LB) and ascorbic acid on I/R-induced liver injury in rats. Liver ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 minutes. Thereafter, flow was restored with reperfusion for 90 minutes. Blood samples collected before ischemia and after reperfusion were analyzed for alanine transaminase (ALT), lactic dehydrogenase (LDH), hydroxyl radical, and nitric oxide (NO) levels. Pharmacologic interventions included administration of ascorbic acid (100 mg/kg, i.p., 1 hour before I/R) or LB, an extract of Gogi berries: 600 mg in 100 mL of drinking water for 2 weeks prior to experimentation. This protocol resulted in elevation of blood concentrations of NO, hydroxyl radical, ALT, and LDH (P &lt; .001) in the I/R-induced liver injury group. Ascorbic acid significantly attenuated the reperfusion liver injury by attenuating hydroxyl radical (P &lt; .01) and NO (P &lt; .05) release. The LB aggravated I/R-induced liver injury by increasing hydroxyl radical release with no effect on NO release. This I/R protocol resulted in oxidative and nitrosative stress and liver injury. Ascorbic acid showed significant protective effects on reperfusion liver injury by attenuating hydroxyl radical and NO release. In contrast, LB aggravated liver injury by increasing hydroxyl radical release.
Our aim was to study the expressions of matrix metalloprotease 9 (MMP9) and the effects of the MM... more Our aim was to study the expressions of matrix metalloprotease 9 (MMP9) and the effects of the MMP inhibitor Ilomastat in both ischemia/reperfusion (I/R)- and oleic acid (OA)-induced lung injury models. Real-time polymerase chain reactions and Western blots were used to assess mRNA and protein expressions of MMP9 in lung tissues after I/R or OA lung injury. Ischemia was induced by clamping one branch of the pulmonary artery for 60 minutes and then reperfusing for 120 minutes. In the OA model, lung injury was induced by intravenous infusion of OA (0.1 mL/kg) for 20 minutes and then observation for 6 hours. Lavage leukocyte concentration and wet/dry lung weight ratio were used to assess lung inflammation and injury. Blood samples were collected for assays of hydroxyl radicals and nitric oxide. The MMP inhibitor Ilomastat (100 microg/kg) was administered before I/R and OA infusion. mRNA and protein expressions of MMP9 were significantly increased in both lung injury models. Ilomastat decreased MMP9 mRNA and protein expressions but did not reach statistical significance. Blood concentrations of hydroxyl radicals and nitric oxide, wet/dry lung weight ratios, and lavage leukocyte concentrations were significantly higher in both experimental groups compared with the sham group (P &lt; .001). Ilomastat significantly attenuated the extent of lung inflammation and injury induced by both I/R and OA. MMP may play a critical role in the lung injury induced by I/R and OA infusion.
Our aim was to study the expression of inducible nitric oxide synthase (iNOS) in 2 experimental m... more Our aim was to study the expression of inducible nitric oxide synthase (iNOS) in 2 experimental models: (1) ischemia/reperfusion (I/R) of the lung tissues and (2) oleic acid infusion. The protective effect of an iNOS inhibitor, aminoguanidine, was evaluated in these 2 injury models. Real-time polymerase chain reactions and Western blots were used to assess the mRNA and protein expressions of iNOS in lung tissues after applying 2 injury models. In the I/R model, ischemia was induced by clamping one branch of the pulmonary artery for 60 minutes and then reperfusing for 120 minutes. In the bone fracture model, lung injury was induced by intravenous (IV) infusion of oleic acid (0.1 mL/kg); analysis was performed 6 hours after injury. Blood samples were collected for the assay of 3 inflammatory parameters: tumor necrosis factor alpha, hydroxyl radicals, and nitric oxide (NO). The wet/dry lung weight ratio was used as a parameter reflecting the lung injury level. mRNA and protein expressions of iNOS were significantly increased in these 2 lung injury models compared with the controls. Blood concentrations of TNFalpha, hydroxyl radicals, NO, and wet/dry lung weight ratio were also significantly higher in the 2 experimental groups than in the sham-treated group. The iNOS inhibitor aminoguanidine (20 mg/kg) significantly attenuated the lung injury induced by these challenges. Reperfusion of the ischemic lung tissues or IV infusion of oleic acid can both induce lung injury by activating systemic inflammatory responses and inducing iNOS expression. Administration of aminoguanidine can significantly attenuate the injury, suggesting that iNOS expression may play a critical role in the lung injury induced in these 2 models.
Background: To retrospectively review the outcome of patients with primary or secondary oligometa... more Background: To retrospectively review the outcome of patients with primary or secondary oligometastatic lung cancer, treated with hypofractionated Tomotherapy. Methods: Between April 2007 and June 2011, a total of 33 patients with oligometastatic intrapulmonary lesions underwent hypofractionated radiotherapy by Tomotherapy along with appropriate systemic therapy. There were 24 primary, and 9 secondary lung cancer cases. The radiation doses ranged from 4.5 to 7.0 Gy per fraction, multiplied by 8-16 fractions. The median dose per fraction was 4.5 Gy (range, 4.5-7.0 Gy), and the median total dose was 49.5 Gy (range, 45-72 Gy). The median estimated biological effective dose at 10 Gy (BED 10 ) was 71.8 Gy (range, 65.3-119.0 Gy), and that at 3 Gy (BED 3 ) was 123.8 Gy (range, 112.5-233.3 Gy). The mean lung dose (MLD) was constrained mainly under 1200 cGy. The median gross tumor volume (GTV) was 27.9 cm 3 (range: 2.5-178.1 cm 3 ).
Melatonin is a free radical scavenger with potent antioxidant properties and immunomodulatory eff... more Melatonin is a free radical scavenger with potent antioxidant properties and immunomodulatory effects. The purpose of this study was to determine the effects of orally administered melatonin in a pancreatic fluid (PF)-induced lung inflammation and airway hyperreactivity model. Aerosolized PF was introduced into airways to induce inflammation in rats. Animals were randomized into three experimental groups: sham treated; PF treated (200 μL/kg); and PF with melatonin (10 mg/kg) pretreatment. Airway reactivity to methacholine, airflow and airway resistance, bronchoalveolar lavage (BAL) cellular differential, the tumor necrosis factor α (TNFα) level, lavage nitric oxide, hydroxyl radical, and lactic dehydrogenase (LDH) were compared among groups. mRNA expressions of inducible nitric oxide synthase (iNOS) and TNFα in lung tissues were determined by real-time polymerase chain reaction. Protein expressions of iNOS and nitrotyrosine and lung tissue myeloperoxidase (MPO) activity were determined using an ELISA assay. Oral melatonin treatment indicated anti-inflammatory efficacy as evidenced by decreased methacholine sensitivity by 24% and airway obstruction by 28%, reduction in BAL eosinophil (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and neutrophil counts (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), LDH (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), and TNFα concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) when compared to levels in sham-treated rats. Melatonin-treated animals also had reduced nitric oxide and hydroxyl radical concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in lavage fluid. Oral melatonin significantly reduced mRNA and protein expression of iNOS (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 and P…
Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effect... more Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effects. We studied the effects of melatonin on changes in lung function, oxidative/nitrosative stress, and inflammatory cell sequestration in an acute pancreatitis (AP)-associated lung inflammation model. Acute pancreatitis was induced by injection of 5% sodium taurocholate into the pancreatic duct of rats. Animals were randomized into control, AP, and a melatonin pretreatment (10 mg/kg)/AP group. Functional residual capacity (FRC), lung compliance (Cchord), expiratory flow rate at 50% (FEF50), airway resistance index (RI), and peak expiratory flow rate (PEF) were evaluated. White blood cell count (WBC) and hydrogen peroxide, lung lavage fluid WBC, methylguanidine, protein, lactic dehydrogenase (LDH), nitric oxide (NO), and leukotriene B4 (LTB4) levels were determined. Lung wet-to-dry weight ratio, peroxynitrite, and inducible nitric oxide synthase (NOS) mRNA and protein were measured. AP induction resulted in reductions in FRC, Cchord, FEF50, and PEF, and increase in RI and lung wet-to-dry weight ratio. Blood and lung lavage fluid WBC, lavage fluid LDH, protein, and blood hydrogen peroxide also increased. Levels of hydroxyl radicals, nitric oxide, and LTB4 in lung lavage fluid, inducible NOS mRNA, protein expression, and peroxynitrite in lung tissue also were significantly elevated. Pretreatment with melatonin attenuated obstructive and restrictive ventilatory insufficiency induced by AP. Blood and lavage WBC, lavage LDH and protein, lung edema, oxidative/nitrosative stress, and lipoxygenase pathway derivatives were also significantly attenuated by melatonin. We conclude that melatonin decreases AP-induced obstructive and restrictive lung function changes via its antioxidant and anti-inflammatory properties.
To describe the clinical characteristics and outcomes of patients with severe acute respiratory s... more To describe the clinical characteristics and outcomes of patients with severe acute respiratory syndrome (SARS). Between March 28 and June 30 &#39;2003, 29 patients with probable SARS seen at Shin Kong Wu Ho-Su Memorial Hospital, Taipei, were analysed. Presenting symptoms included fever (100%), cough (69.0%), chills or rigor (62.1%), and shortness of breath (41.4%). Mean days to defervescence were 6.8+/-2.9 days, but fever recurred in 15 patients (51.7%) at 10.9+/-3.4 days. Common laboratory features included lymphopenia (72.4%), thrombocytopenia (34.5%) and elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) (93.1, 62.1, 44.8%, respectively). All patients except one had initial abnormal chest radiographs and 20 (69.0%) had radiological worsening at 7.5+/-2.6 days. Nine patients (31.0%) subsequently required mechanical ventilation with four deaths (13.8%). Most patients with clinical deterioration responded to pulse corticosteroid therapy (14 out of 17) but six complicated with nosocomial infections. The risk factors associated with severe disease were presence of diarrhoea, high peak LDH and CRP, high AST and creatine kinase on admission and high peak values. Prudent corticosteroid use, vigilant microbiological surveillance and appropriate antibiotics coverage are the key to successful treatment.
We aim to test the hypothesis that hypercalcemia produces pulmonary edema (PE) and to elucidate t... more We aim to test the hypothesis that hypercalcemia produces pulmonary edema (PE) and to elucidate the mechanism. Experimentations were carried out in conscious rats and isolated perfused rat lungs. We evaluated PE by lung weight changes, protein concentration in bronchoalveolar lavage, dye leakage, and microvascular permeability. Plasma nitrate/nitrite, methyl guanidine (MG), proinflammatory cytokines, procalcitonin levels, and histopathological examinations were evaluated. Immunochemical staining and reverse-transcriptase polymerase chain reaction (RT-PCR) were used to detect inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in the lungs. Hypercalcemia was produced in the conscious rat and isolated perfused lungs. Calcitonin and L-N(6) (1-iminoethyl)-lysine (L-Nil) were administered before hypercalcemia to observe their effects. Hypercalcemia caused severe PE in rats. Pathological and immunochemical examinations revealed hemorrhagic edema with iNOS activity in the alveolar macrophages and epithelial cells. RT-PCR showed an increase in iNOS mRNA expression. Hypercalcemia increased nitrate/nitrite, MG, proinflammatory cytokines and procalcitonin levels. Pretreatment with calcitonin or L-Nil prevented these changes. In conclusion, hypercalcemia caused PE in conscious rats and isolated perfused rat lungs. The increases in nitrate/nitrite, free radicals, proinflammatory cytokines, procalcitonin and iNOS activity suggest that hypercalcemia induces a sepsis-like syndrome. The effect of hypercalcemia on the lung may involve iNOS and NO.
Delayed diagnosis of pyogenic liver abscess remains a challenging problem in the emergency depart... more Delayed diagnosis of pyogenic liver abscess remains a challenging problem in the emergency department because of the associated high morbidity and mortality. To evaluate the sensitivity of ultrasono-graphy in the diagnosis of pyogenic liver abscess in patients presenting to the emergency department and the factors that may influence this sensitivity. A retrospective study was conducted in patients diagnosed with pyogenic liver abscess in the emergency department (ED) of a tertiary care teaching hospital for a period of 5 years. Between May 2001 and April 2006, 268 patients diagnosed with pyogenic liver abscess were evaluated by ultrasonography and/or CT scanning. The age, sex, clinical presentation, location and number of abscesses and the underlying disease of these two groups were compared. Of the 268 patients admitted via the ED who were discharged or died with a diagnosis of pyogenic liver abscess, there was a predominance of men (M/F 173/95) and the mean age was 57.6 years (range 17-90). 38 had false negative findings on ultrasonography (sensitivity 85.8%) and required abdominal CT scanning for definitive diagnosis. In the other 230 cases, ultrasonography alone was sufficient for diagnosis. Location of the abscess in segments 4 and 5 of the liver raised the sensitivity of ultrasound for diagnosis, while location in segment 8 was most associated with delayed diagnosis by ultrasonography. Right costal angle knocking pain was significant for pyogenic liver abscess even if ultrasound was negative. The size and location of the liver abscess and the underlying comorbid diseases may affect the diagnostic sensitivity of ultrasound for pyogenic liver abscess in clinical practice. A high index of suspicion should be maintained in patients with diabetes mellitus, previous biliary tract intervention or gastrointestinal malignancy. Follow-up CT scanning is recommended if right flank knocking pain is present, even if ultrasonography is non-revealing. A diagnostic protocol for liver abscess may be feasible in the future.
To investigate the effects of insulin on the acute lung injury induced by lipopolysaccharide usin... more To investigate the effects of insulin on the acute lung injury induced by lipopolysaccharide using a conscious rat model. Prospective, randomized, controlled animal study. University research laboratory. A total of 190 adult male Sprague-Dawley rats weighing 250-300 g. Endotoxemia was induced by intravenous infusion of lipopolysaccharide. Lipopolysaccharide at various doses (0, 1, 5, 10, 20, and 30 mg/kg, n=10 for each dose) was administered intravenously in 20 mins. Insulin infusion at doses of 0.5, 1, and 5 microU/kg/min was given 5 mins before lipopolysaccharide administration. Plasma glucose was clamped at 90-110 mg/dL by infusion of 10-80% glucose solution. Insulin and glucose infusion (0.01 mL/min) was started 5 mins before lipopolysaccharide and continued for 120 mins. The rats received a total of 60, 120, and 600 microU/kg insulin as well as 0.12, 0.36, and 0.96 g of glucose in respective groups. The animals were then observed for 4 hrs. The extent of acute lung injury was evaluated by lung weight/body weight ratio, lung weight gain, protein concentration in bronchoalveolar lavage, and exhaled nitric oxide. We also measured plasma nitrate/nitrite and methyl guanidine. In addition, histopathologic changes of the lung were examined. Lipopolysaccharide caused systemic hypotension and severe acute lung injury with increases in plasma nitrate/nitrite and methyl guanidine. Pretreatment with insulin infusion at doses of 0.5, 1, and 5 microU/kg/min mitigated or prevented systemic hypotension and the development of acute lung injury, depending on the dose. Insulin also attenuated the lipopolysaccharide-induced increases in nitrate/nitrite and methyl guanidine. Insulin is effective in reducing or preventing the lipopolysaccharide-induced increases in plasma nitrate/nitrite and methyl guanidine and the occurrence of acute lung injury.
FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress... more FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress syndrome) has been considered as a serious complication of FES, the pathogenesis of ARDS associated with FES remains unclear. In the present study, we investigated the clinical manifestations, and biochemical and pathophysiological changes, in subjects associated with FES and ARDS, to elucidate the possible mechanisms involved in this disorder. A total of eight patients with FES were studied, and arterial blood pH, PaO(2) (arterial partial pressure of O(2)), PaCO(2) (arterial partial pressure of CO(2)), biochemical and pathophysiological data were obtained. These subjects suffered from crash injuries and developed FES associated with ARDS, and each died within 2 h after admission. In the subjects, chest radiography revealed that the lungs were clear on admission, and pulmonary infiltration was observed within 2 h of admission. Arterial blood pH and PaO(2) declined, whereas PaCO(2) increased. Plasma PLA(2) (phospholipase A(2)), nitrate/nitrite, methylguanidine, TNF-alpha (tumour necrosis factor-alpha), IL-1beta (interleukin-1beta) and IL-10 (interleukin-10) were significantly elevated. Pathological examinations revealed alveolar oedema and haemorrhage with multiple fat droplet depositions and fibrin thrombi. Fat droplets were also found in the arterioles and/or capillaries in the lung, kidney and brain. Immunohistochemical staining identified iNOS (inducible nitric oxide synthase) in alveolar macrophages. In conclusion, our clinical analysis suggests that PLA(2), NO, free radicals and pro-inflammatory cytokines are involved in the pathogenesis of ARDS associated with FES. The major source of NO is the alveolar macrophages.
Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. ... more Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage. A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ. In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed. I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage. The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.
Poor growth is a common feature of symptomatic children (Centers for Disease Control stage P2) in... more Poor growth is a common feature of symptomatic children (Centers for Disease Control stage P2) infected with human immunodeficiency virus-1 (HIV-1). However, several previous studies have failed to show any relationship between serum hormone levels and poor growth. To assess the roles of hormone deficiency and hormone resistance in the development of poor growth in HIV-1-infected children, we studied six asymptomatic Centers for Disease Control stage P I [height SD score = 0.01 + 1.0 (mean 2 SD)], 10 P2 (height SD score = -2.0 + 1.0), and six short, normal children (height S D score = -2.4 + 1.2). Mean weighkheight SD scores were similar in all three groups, suggesting that gross nutritional status did not differ between groups. There were no significant differences between groups with respect to mean plasma levels of IGF-I, thyroid hormones, TSH, and cortisol. As an index of hormone sensitivity, we quantified in vhro colony formation of erythroid progenitor cells, isolated from peripheral blood of study subjects, in response to IGF-I, growth hormone (GII), and insulin. 1' 2 subjects hnd a quantitative mean reduction in erythroid progenitor cells colony formation in response to IGF-I of 32% compared with PI subjects ( p = 0.001 by analysis of variance) and 21% compared with controls (p = 0.006); in rcsponsc to GH of 21% compared with controls (p = 0.015); and in response to insulin of 35% compared with PI subjects (p = 0.038) and 34% compared with controls ( p = 0.004). Similar qualitative differences (changes in shape) of the three hormone response curves between P2 and P1 and P2 and control subjects were observed. No differences in either quantitative or qualitative erythroid progenitor cells responses to IGF-I, GH, or insulin between P1 and control subjects were observed. We conclude that more severe HIV-1 infection in children is associated with in vitro resistance to the growth-promoting actions of IGF-I, GH, and insulin that is unrelated to the presence of gross malnutrition, differences in hematologic status, or over-
Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia o... more Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in >90% FIO2 for
Pleomorphic carcinoma is an extremely rare histological type of lung malignancy. Although it carr... more Pleomorphic carcinoma is an extremely rare histological type of lung malignancy. Although it carries an aggressive clinical course, intracardiac extension has never been reported before. We describe a 53-year-old lady presented to our emergency department with progressive shortness of breath and intermittent fever for six weeks. After detailed work-up, a lung tumor with intracardiac extension via pulmonary vein to the left atrium was disclosed. Pathologic examination of a computerized tomography-guided lung biopsy showed pleomorphic carcinoma. The patient underwent wide excision of the left atrial tumor and subsequent right pneumonectomy smoothly. Both the left atrial and lung tumors showed the same histologic picture of pleomorphic carcinoma. However, brain metastasis was disclosed three months after operation. The patient eventually died of severe sepsis six months later.
Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer p... more Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer patients in Taiwan. We hypothesized that early integration of radiotherapy during TKI treatment would decrease the chance of drug resistance and prolong progression-free survival (PFS). This study included 25 patients with stage IIIb or IV non-squamous cell, non-small cell lung cancer (NSqCLC) who responded to upfront TKI treatment. Multi-target radiotherapy was administered during the TKI treatment course. Tomotherapy comprising a hypofractionated schedule with a dose of 40-50 Gy in 16-20 fractions was used for individual metastatic lesions. The patients' median follow-up duration was 30 months (range, 9-62 months). Of the 23 patients who had stage IV disease, 9 had oligometastases (≤5 gross target volumes) and 14 were in the more advanced stages of the disease. Twelve patients received more than 1 cycle of radiotherapy (median, 3; range, 2-6) with TKI being the only systemic treatme...
Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia o... more Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challeng...
Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal inj... more Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals;...
Ischemia/reperfusion (I/R) of the rat liver can induce liver injury through mechanisms involving ... more Ischemia/reperfusion (I/R) of the rat liver can induce liver injury through mechanisms involving oxidative and nitrosative stresses. In this study we examined the effects of antioxidants Lycium barbarum (LB) and ascorbic acid on I/R-induced liver injury in rats. Liver ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 minutes. Thereafter, flow was restored with reperfusion for 90 minutes. Blood samples collected before ischemia and after reperfusion were analyzed for alanine transaminase (ALT), lactic dehydrogenase (LDH), hydroxyl radical, and nitric oxide (NO) levels. Pharmacologic interventions included administration of ascorbic acid (100 mg/kg, i.p., 1 hour before I/R) or LB, an extract of Gogi berries: 600 mg in 100 mL of drinking water for 2 weeks prior to experimentation. This protocol resulted in elevation of blood concentrations of NO, hydroxyl radical, ALT, and LDH (P &lt; .001) in the I/R-induced liver injury group. Ascorbic acid significantly attenuated the reperfusion liver injury by attenuating hydroxyl radical (P &lt; .01) and NO (P &lt; .05) release. The LB aggravated I/R-induced liver injury by increasing hydroxyl radical release with no effect on NO release. This I/R protocol resulted in oxidative and nitrosative stress and liver injury. Ascorbic acid showed significant protective effects on reperfusion liver injury by attenuating hydroxyl radical and NO release. In contrast, LB aggravated liver injury by increasing hydroxyl radical release.
Our aim was to study the expressions of matrix metalloprotease 9 (MMP9) and the effects of the MM... more Our aim was to study the expressions of matrix metalloprotease 9 (MMP9) and the effects of the MMP inhibitor Ilomastat in both ischemia/reperfusion (I/R)- and oleic acid (OA)-induced lung injury models. Real-time polymerase chain reactions and Western blots were used to assess mRNA and protein expressions of MMP9 in lung tissues after I/R or OA lung injury. Ischemia was induced by clamping one branch of the pulmonary artery for 60 minutes and then reperfusing for 120 minutes. In the OA model, lung injury was induced by intravenous infusion of OA (0.1 mL/kg) for 20 minutes and then observation for 6 hours. Lavage leukocyte concentration and wet/dry lung weight ratio were used to assess lung inflammation and injury. Blood samples were collected for assays of hydroxyl radicals and nitric oxide. The MMP inhibitor Ilomastat (100 microg/kg) was administered before I/R and OA infusion. mRNA and protein expressions of MMP9 were significantly increased in both lung injury models. Ilomastat decreased MMP9 mRNA and protein expressions but did not reach statistical significance. Blood concentrations of hydroxyl radicals and nitric oxide, wet/dry lung weight ratios, and lavage leukocyte concentrations were significantly higher in both experimental groups compared with the sham group (P &lt; .001). Ilomastat significantly attenuated the extent of lung inflammation and injury induced by both I/R and OA. MMP may play a critical role in the lung injury induced by I/R and OA infusion.
Our aim was to study the expression of inducible nitric oxide synthase (iNOS) in 2 experimental m... more Our aim was to study the expression of inducible nitric oxide synthase (iNOS) in 2 experimental models: (1) ischemia/reperfusion (I/R) of the lung tissues and (2) oleic acid infusion. The protective effect of an iNOS inhibitor, aminoguanidine, was evaluated in these 2 injury models. Real-time polymerase chain reactions and Western blots were used to assess the mRNA and protein expressions of iNOS in lung tissues after applying 2 injury models. In the I/R model, ischemia was induced by clamping one branch of the pulmonary artery for 60 minutes and then reperfusing for 120 minutes. In the bone fracture model, lung injury was induced by intravenous (IV) infusion of oleic acid (0.1 mL/kg); analysis was performed 6 hours after injury. Blood samples were collected for the assay of 3 inflammatory parameters: tumor necrosis factor alpha, hydroxyl radicals, and nitric oxide (NO). The wet/dry lung weight ratio was used as a parameter reflecting the lung injury level. mRNA and protein expressions of iNOS were significantly increased in these 2 lung injury models compared with the controls. Blood concentrations of TNFalpha, hydroxyl radicals, NO, and wet/dry lung weight ratio were also significantly higher in the 2 experimental groups than in the sham-treated group. The iNOS inhibitor aminoguanidine (20 mg/kg) significantly attenuated the lung injury induced by these challenges. Reperfusion of the ischemic lung tissues or IV infusion of oleic acid can both induce lung injury by activating systemic inflammatory responses and inducing iNOS expression. Administration of aminoguanidine can significantly attenuate the injury, suggesting that iNOS expression may play a critical role in the lung injury induced in these 2 models.
Background: To retrospectively review the outcome of patients with primary or secondary oligometa... more Background: To retrospectively review the outcome of patients with primary or secondary oligometastatic lung cancer, treated with hypofractionated Tomotherapy. Methods: Between April 2007 and June 2011, a total of 33 patients with oligometastatic intrapulmonary lesions underwent hypofractionated radiotherapy by Tomotherapy along with appropriate systemic therapy. There were 24 primary, and 9 secondary lung cancer cases. The radiation doses ranged from 4.5 to 7.0 Gy per fraction, multiplied by 8-16 fractions. The median dose per fraction was 4.5 Gy (range, 4.5-7.0 Gy), and the median total dose was 49.5 Gy (range, 45-72 Gy). The median estimated biological effective dose at 10 Gy (BED 10 ) was 71.8 Gy (range, 65.3-119.0 Gy), and that at 3 Gy (BED 3 ) was 123.8 Gy (range, 112.5-233.3 Gy). The mean lung dose (MLD) was constrained mainly under 1200 cGy. The median gross tumor volume (GTV) was 27.9 cm 3 (range: 2.5-178.1 cm 3 ).
Melatonin is a free radical scavenger with potent antioxidant properties and immunomodulatory eff... more Melatonin is a free radical scavenger with potent antioxidant properties and immunomodulatory effects. The purpose of this study was to determine the effects of orally administered melatonin in a pancreatic fluid (PF)-induced lung inflammation and airway hyperreactivity model. Aerosolized PF was introduced into airways to induce inflammation in rats. Animals were randomized into three experimental groups: sham treated; PF treated (200 μL/kg); and PF with melatonin (10 mg/kg) pretreatment. Airway reactivity to methacholine, airflow and airway resistance, bronchoalveolar lavage (BAL) cellular differential, the tumor necrosis factor α (TNFα) level, lavage nitric oxide, hydroxyl radical, and lactic dehydrogenase (LDH) were compared among groups. mRNA expressions of inducible nitric oxide synthase (iNOS) and TNFα in lung tissues were determined by real-time polymerase chain reaction. Protein expressions of iNOS and nitrotyrosine and lung tissue myeloperoxidase (MPO) activity were determined using an ELISA assay. Oral melatonin treatment indicated anti-inflammatory efficacy as evidenced by decreased methacholine sensitivity by 24% and airway obstruction by 28%, reduction in BAL eosinophil (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and neutrophil counts (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), LDH (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), and TNFα concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) when compared to levels in sham-treated rats. Melatonin-treated animals also had reduced nitric oxide and hydroxyl radical concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in lavage fluid. Oral melatonin significantly reduced mRNA and protein expression of iNOS (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05 and P…
Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effect... more Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effects. We studied the effects of melatonin on changes in lung function, oxidative/nitrosative stress, and inflammatory cell sequestration in an acute pancreatitis (AP)-associated lung inflammation model. Acute pancreatitis was induced by injection of 5% sodium taurocholate into the pancreatic duct of rats. Animals were randomized into control, AP, and a melatonin pretreatment (10 mg/kg)/AP group. Functional residual capacity (FRC), lung compliance (Cchord), expiratory flow rate at 50% (FEF50), airway resistance index (RI), and peak expiratory flow rate (PEF) were evaluated. White blood cell count (WBC) and hydrogen peroxide, lung lavage fluid WBC, methylguanidine, protein, lactic dehydrogenase (LDH), nitric oxide (NO), and leukotriene B4 (LTB4) levels were determined. Lung wet-to-dry weight ratio, peroxynitrite, and inducible nitric oxide synthase (NOS) mRNA and protein were measured. AP induction resulted in reductions in FRC, Cchord, FEF50, and PEF, and increase in RI and lung wet-to-dry weight ratio. Blood and lung lavage fluid WBC, lavage fluid LDH, protein, and blood hydrogen peroxide also increased. Levels of hydroxyl radicals, nitric oxide, and LTB4 in lung lavage fluid, inducible NOS mRNA, protein expression, and peroxynitrite in lung tissue also were significantly elevated. Pretreatment with melatonin attenuated obstructive and restrictive ventilatory insufficiency induced by AP. Blood and lavage WBC, lavage LDH and protein, lung edema, oxidative/nitrosative stress, and lipoxygenase pathway derivatives were also significantly attenuated by melatonin. We conclude that melatonin decreases AP-induced obstructive and restrictive lung function changes via its antioxidant and anti-inflammatory properties.
To describe the clinical characteristics and outcomes of patients with severe acute respiratory s... more To describe the clinical characteristics and outcomes of patients with severe acute respiratory syndrome (SARS). Between March 28 and June 30 &#39;2003, 29 patients with probable SARS seen at Shin Kong Wu Ho-Su Memorial Hospital, Taipei, were analysed. Presenting symptoms included fever (100%), cough (69.0%), chills or rigor (62.1%), and shortness of breath (41.4%). Mean days to defervescence were 6.8+/-2.9 days, but fever recurred in 15 patients (51.7%) at 10.9+/-3.4 days. Common laboratory features included lymphopenia (72.4%), thrombocytopenia (34.5%) and elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) (93.1, 62.1, 44.8%, respectively). All patients except one had initial abnormal chest radiographs and 20 (69.0%) had radiological worsening at 7.5+/-2.6 days. Nine patients (31.0%) subsequently required mechanical ventilation with four deaths (13.8%). Most patients with clinical deterioration responded to pulse corticosteroid therapy (14 out of 17) but six complicated with nosocomial infections. The risk factors associated with severe disease were presence of diarrhoea, high peak LDH and CRP, high AST and creatine kinase on admission and high peak values. Prudent corticosteroid use, vigilant microbiological surveillance and appropriate antibiotics coverage are the key to successful treatment.
We aim to test the hypothesis that hypercalcemia produces pulmonary edema (PE) and to elucidate t... more We aim to test the hypothesis that hypercalcemia produces pulmonary edema (PE) and to elucidate the mechanism. Experimentations were carried out in conscious rats and isolated perfused rat lungs. We evaluated PE by lung weight changes, protein concentration in bronchoalveolar lavage, dye leakage, and microvascular permeability. Plasma nitrate/nitrite, methyl guanidine (MG), proinflammatory cytokines, procalcitonin levels, and histopathological examinations were evaluated. Immunochemical staining and reverse-transcriptase polymerase chain reaction (RT-PCR) were used to detect inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in the lungs. Hypercalcemia was produced in the conscious rat and isolated perfused lungs. Calcitonin and L-N(6) (1-iminoethyl)-lysine (L-Nil) were administered before hypercalcemia to observe their effects. Hypercalcemia caused severe PE in rats. Pathological and immunochemical examinations revealed hemorrhagic edema with iNOS activity in the alveolar macrophages and epithelial cells. RT-PCR showed an increase in iNOS mRNA expression. Hypercalcemia increased nitrate/nitrite, MG, proinflammatory cytokines and procalcitonin levels. Pretreatment with calcitonin or L-Nil prevented these changes. In conclusion, hypercalcemia caused PE in conscious rats and isolated perfused rat lungs. The increases in nitrate/nitrite, free radicals, proinflammatory cytokines, procalcitonin and iNOS activity suggest that hypercalcemia induces a sepsis-like syndrome. The effect of hypercalcemia on the lung may involve iNOS and NO.
Delayed diagnosis of pyogenic liver abscess remains a challenging problem in the emergency depart... more Delayed diagnosis of pyogenic liver abscess remains a challenging problem in the emergency department because of the associated high morbidity and mortality. To evaluate the sensitivity of ultrasono-graphy in the diagnosis of pyogenic liver abscess in patients presenting to the emergency department and the factors that may influence this sensitivity. A retrospective study was conducted in patients diagnosed with pyogenic liver abscess in the emergency department (ED) of a tertiary care teaching hospital for a period of 5 years. Between May 2001 and April 2006, 268 patients diagnosed with pyogenic liver abscess were evaluated by ultrasonography and/or CT scanning. The age, sex, clinical presentation, location and number of abscesses and the underlying disease of these two groups were compared. Of the 268 patients admitted via the ED who were discharged or died with a diagnosis of pyogenic liver abscess, there was a predominance of men (M/F 173/95) and the mean age was 57.6 years (range 17-90). 38 had false negative findings on ultrasonography (sensitivity 85.8%) and required abdominal CT scanning for definitive diagnosis. In the other 230 cases, ultrasonography alone was sufficient for diagnosis. Location of the abscess in segments 4 and 5 of the liver raised the sensitivity of ultrasound for diagnosis, while location in segment 8 was most associated with delayed diagnosis by ultrasonography. Right costal angle knocking pain was significant for pyogenic liver abscess even if ultrasound was negative. The size and location of the liver abscess and the underlying comorbid diseases may affect the diagnostic sensitivity of ultrasound for pyogenic liver abscess in clinical practice. A high index of suspicion should be maintained in patients with diabetes mellitus, previous biliary tract intervention or gastrointestinal malignancy. Follow-up CT scanning is recommended if right flank knocking pain is present, even if ultrasonography is non-revealing. A diagnostic protocol for liver abscess may be feasible in the future.
To investigate the effects of insulin on the acute lung injury induced by lipopolysaccharide usin... more To investigate the effects of insulin on the acute lung injury induced by lipopolysaccharide using a conscious rat model. Prospective, randomized, controlled animal study. University research laboratory. A total of 190 adult male Sprague-Dawley rats weighing 250-300 g. Endotoxemia was induced by intravenous infusion of lipopolysaccharide. Lipopolysaccharide at various doses (0, 1, 5, 10, 20, and 30 mg/kg, n=10 for each dose) was administered intravenously in 20 mins. Insulin infusion at doses of 0.5, 1, and 5 microU/kg/min was given 5 mins before lipopolysaccharide administration. Plasma glucose was clamped at 90-110 mg/dL by infusion of 10-80% glucose solution. Insulin and glucose infusion (0.01 mL/min) was started 5 mins before lipopolysaccharide and continued for 120 mins. The rats received a total of 60, 120, and 600 microU/kg insulin as well as 0.12, 0.36, and 0.96 g of glucose in respective groups. The animals were then observed for 4 hrs. The extent of acute lung injury was evaluated by lung weight/body weight ratio, lung weight gain, protein concentration in bronchoalveolar lavage, and exhaled nitric oxide. We also measured plasma nitrate/nitrite and methyl guanidine. In addition, histopathologic changes of the lung were examined. Lipopolysaccharide caused systemic hypotension and severe acute lung injury with increases in plasma nitrate/nitrite and methyl guanidine. Pretreatment with insulin infusion at doses of 0.5, 1, and 5 microU/kg/min mitigated or prevented systemic hypotension and the development of acute lung injury, depending on the dose. Insulin also attenuated the lipopolysaccharide-induced increases in nitrate/nitrite and methyl guanidine. Insulin is effective in reducing or preventing the lipopolysaccharide-induced increases in plasma nitrate/nitrite and methyl guanidine and the occurrence of acute lung injury.
FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress... more FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress syndrome) has been considered as a serious complication of FES, the pathogenesis of ARDS associated with FES remains unclear. In the present study, we investigated the clinical manifestations, and biochemical and pathophysiological changes, in subjects associated with FES and ARDS, to elucidate the possible mechanisms involved in this disorder. A total of eight patients with FES were studied, and arterial blood pH, PaO(2) (arterial partial pressure of O(2)), PaCO(2) (arterial partial pressure of CO(2)), biochemical and pathophysiological data were obtained. These subjects suffered from crash injuries and developed FES associated with ARDS, and each died within 2 h after admission. In the subjects, chest radiography revealed that the lungs were clear on admission, and pulmonary infiltration was observed within 2 h of admission. Arterial blood pH and PaO(2) declined, whereas PaCO(2) increased. Plasma PLA(2) (phospholipase A(2)), nitrate/nitrite, methylguanidine, TNF-alpha (tumour necrosis factor-alpha), IL-1beta (interleukin-1beta) and IL-10 (interleukin-10) were significantly elevated. Pathological examinations revealed alveolar oedema and haemorrhage with multiple fat droplet depositions and fibrin thrombi. Fat droplets were also found in the arterioles and/or capillaries in the lung, kidney and brain. Immunohistochemical staining identified iNOS (inducible nitric oxide synthase) in alveolar macrophages. In conclusion, our clinical analysis suggests that PLA(2), NO, free radicals and pro-inflammatory cytokines are involved in the pathogenesis of ARDS associated with FES. The major source of NO is the alveolar macrophages.
Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. ... more Ischemia (I)/reperfusion (R) lung injury is an important clinical issue in lung transplantation. In the present study, we observed the effects of lung static inflation, different perfusates, and ventilatory gas with nitrogen or oxygen on the I/R-induced pulmonary damage. A total of 96 male Sprague-Dawley rats were used. The lung was isolated in situ. In an isolated lung, the capillary filtration coefficient (Kfc), lung weight gain (LWG), lung weight (LW)/body weight (BW) ratio, and protein concentration in BAL fluid (PCBAL) were measured or calculated to evaluate the degree of lung injury. Histologic examinations with hematoxylin-eosin staining were performed. I/R caused lung injury, as reflected by increases in Kfc, LWG, LW/BW, and PCBAL. The histopathologic picture revealed the presence of hyaline membrane formation and the infiltration of inflammatory cells. These values were significantly attenuated by static lung inflation. The I/R lung damage appeared to be less in the lung perfused with whole blood than in the lung perfused with an isotonic solution. Therapy with ventilatory air (ie, nitrogen or oxygen) did not alter the I/R lung damage. The data suggest that lung inflation is protective to I/R injury, irrespective of the type of ventilatory air used for treatment. The preservation of the lung for transplantation is better kept at a static inflation state and perfused with whole blood instead of an isotonic physiologic solution.
Poor growth is a common feature of symptomatic children (Centers for Disease Control stage P2) in... more Poor growth is a common feature of symptomatic children (Centers for Disease Control stage P2) infected with human immunodeficiency virus-1 (HIV-1). However, several previous studies have failed to show any relationship between serum hormone levels and poor growth. To assess the roles of hormone deficiency and hormone resistance in the development of poor growth in HIV-1-infected children, we studied six asymptomatic Centers for Disease Control stage P I [height SD score = 0.01 + 1.0 (mean 2 SD)], 10 P2 (height SD score = -2.0 + 1.0), and six short, normal children (height S D score = -2.4 + 1.2). Mean weighkheight SD scores were similar in all three groups, suggesting that gross nutritional status did not differ between groups. There were no significant differences between groups with respect to mean plasma levels of IGF-I, thyroid hormones, TSH, and cortisol. As an index of hormone sensitivity, we quantified in vhro colony formation of erythroid progenitor cells, isolated from peripheral blood of study subjects, in response to IGF-I, growth hormone (GII), and insulin. 1' 2 subjects hnd a quantitative mean reduction in erythroid progenitor cells colony formation in response to IGF-I of 32% compared with PI subjects ( p = 0.001 by analysis of variance) and 21% compared with controls (p = 0.006); in rcsponsc to GH of 21% compared with controls (p = 0.015); and in response to insulin of 35% compared with PI subjects (p = 0.038) and 34% compared with controls ( p = 0.004). Similar qualitative differences (changes in shape) of the three hormone response curves between P2 and P1 and P2 and control subjects were observed. No differences in either quantitative or qualitative erythroid progenitor cells responses to IGF-I, GH, or insulin between P1 and control subjects were observed. We conclude that more severe HIV-1 infection in children is associated with in vitro resistance to the growth-promoting actions of IGF-I, GH, and insulin that is unrelated to the presence of gross malnutrition, differences in hematologic status, or over-
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