Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats

The present study was designed to examine the combined effects of a synthetic protease inhibitor, gabexate mesilate, with a specific neutrophil elastase inhibitor, sivelestat sodium, on acid-induced lung injury. Adult male Sprague-Dawley rats weighing 300-350 g were anaesthetised intraperitoneally with pentobarbitone sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1 N 1.5 ml/kg) or normal saline. Gabexate mesilate (10 mg/kg, i.p.) and/or sivelestat sodium (10 mg/kg/h, i.v.) were administered 30 min before HCl instillation. Bronchoalveolar lavage fluid samples were obtained 5 h after HCl instillation. in bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm as an index of pulmonary haemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not show additive effects on HO-induced lung injury, compared with single treatments. These findings suggested that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, but that synergistic effects of both agents are limited in this acid-induced lung injury model.ArticleEUROPEAN JOURNAL OF PHARMACOLOGY. 641(2-3):220-225 (2010)journal articl

Comparison of acid-induced inflammatory responses in the rat lung during high frequency oscillatory and conventional mechanical ventilation

The present study was performed to compare the effects of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CMV) on pulmonary inflammatory responses in a rat acid-induced lung injury model. Anesthetized rats were instilled intratracheally with HCl (0.1 N, 2 mL/kg) and then randomly divided into three mechanical ventilation settings: HFOV (an oscillatory frequency of 15 Hz, mean airway pressure (MAP) of 9 cmH(2)O), CMV at tidal volume of 12 and 6 mL/kg for 5 h. After HCl instillation, HFOV significantly attenuated the increases in neutrophil infiltration and TNF-alpha concentration in bronchoalveolar lavage fluid compared with the CMV groups. During HFOV, there was an inhibition of an increase in TNF-alpha mRNA expression and a decrease in SP-A mRNA expression induced by acid instillation. This animal study demonstrates that HFOV is a suitable form of mechanical ventilation to prevent inflammatory responses in acid-induced lung injury.ArticleINFLAMMATION RESEARCH. 59(11):931-937 (2010)journal articl

Phase II Trial of Biweekly Paclitaxel and Gemcitabine as Second-Line Chemotherapy for Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy

A phase II study was conducted to evaluate the feasibility and efficacy of biweekly administration of paclitaxel and gemcitabine in patients with non-small cell lung cancer (NSCLC) who had been treated previously with platinum-based chemotherapy. Paclitaxel (150 mg/m2) and gemcitabine (1,000 mg/m2) were administered biweekly for at least 4 cycles. Thirty-one patients with a median age of 64 years (39-75 years) were enrolled in this study(stage IIIB/IV :11/20,PS 0/1/2:13/16/2).Partial response was observed in 7 cases (23%), and stable disease was seen in 18 cases (58%).Median survival time was 8.8 months with a one-year survival rate of 41.9 %.Hematological toxicities were mild and neutropenia of grade 3 or above was observed in one patient (3%). Non-hematological toxicities were also mild, including neurotoxicity (3%). Biweekly paclitaxel and gemcitabine combination chemotherapy was effective and tolerated well as second-line therapy against NSCLC.Article信州医学雑誌 59(6): 411-418(2011)departmental bulletin pape

Exogenous surfactant instillation attenuates inflammatory response to acid-induced lung injury in rat

The present study was performed to investigate the role of exogenous surfactant on hydrochloric acid (HCL) - induced lung injury in rats. Six-week-old male Sprague-Dawley rats were anesthetized by intraperitoneal injection of pentobarbital sodium (40 mg/kg) and HCL (0.1 N, 2 mL/kg) or normal saline (NS, 2 mL/kg) was instilled into the trachea. Thirty minutes after HCL instillation, surfactant at a dose of 60 mg (=2 mL)/body or NS (2 mL) was instilled into the rat lungs. Animals in another experimental group were also treated with the same dose of surfactant supplement 2 hours after the first administration. Bronchoalveolar lavage fluid (BALF) was obtained 5 hours after HCL instillation. In BALF, increases in total nuclear cell counts, neutrophil counts, optical density at 412 nm as an indicator Of Pulmonary hemorrhage, neutrophil elastase activity, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) induced by HCL instillation were significantly attenuated by surfactant treatment. The wet-to-dry weight (W/D) ratio in the lung and partial oxygen tension (P-O2) were also estimated; surfactant treatment significantly attenuated the W/D ratio and improved deteriorated P-O2 induced by HCL Additional surfactant supplementation did not show further beneficial effects on HCL-induced lung injury compared with a single treatment. These results suggest that surfactant shows an anti-inflammatory effect on acid lung injury in rats but the beneficial effects may be dose limited.ArticlePULMONARY PHARMACOLOGY & THERAPEUTICS. 23(1):43-47 (2010)journal articl

Iodine-123 metaiodobenzylguanidine scintigraphic assessment of pulmonary vascular status in patients with chronic obstructive pulmonary disease

Background and objective: Lung uptake of iodine-123 metaiodobenzylguanidine ((123)I-MIBG) is used as an indicator of pulmonary endothelial function. Decreased lung uptake of (123)I-MIBG has been demonstrated in patients with COPD as compared with normal subjects. The present study was performed to examine the relationship between lung uptake of (123)I-MIBG and pulmonary artery pressure (Ppa) at rest and during exercise, in patients with COPD. Methods: (123)I-MIBG scintigraphy was performed in 19 patients with COPD. Anterior planar images were acquired 15 min after the injection of (123)I-MIBG, and the total lung to upper mediastinum ratio (LMR) was calculated for both lungs. Right heart catheters were used to monitor Ppa continuously at rest and during exercise. Exercise was performed on an electrically braked bicycle ergometer at a constant workload of 25 W for 3 min. Results: In COPD patients the LMR were not correlated with the pulmonary function parameters measured before exercise, including FEV(1), PaO(2), DL(CO), or Ppa at rest. However, the percentage increase in Ppa during exercise was significantly correlated with LMR. Conclusions: Evaluation of the kinetics of lung uptake of (123)I-MIBG may be a novel scintigraphic tool for the assessment of exercise-induced pulmonary hypertension in patients with COPD.ArticleRESPIROLOGY. 15(8):1215-1219 (2010)journal articl

Increased isoprostane levels in oleic acid-induced lung injury

The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2 alpha). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.ArticleBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 388(2):297-300 (2009)journal articl

The depletion of donor macrophages reduces ischaemia-reperfusion injury after mouse lung transplantation†

OBJECTIVES Macrophages (M) are one of the most important cells of the innate immune system for first line defense. Upon transplantation (Tx), M play a prominent role during lung ischaemia reperfusion (I/R) injury. Here, we hypothesize that the depletion of donor M ameliorates the post-transplant lung I/R injury. METHODS Orthotopic single-lung Tx was performed between syngeneic BALB/c mice after a cold ischaemic time of 8 h and a reperfusion time of 10 h. Prior to graft implantation, alveolar macrophages of donor lungs were selectively depleted applying the ‘suicide technique' by intratracheal application of clodronate liposomes (experimental, n = 6) vs the application of empty liposomes (control, n = 6). Cell count (number of F4/80+-macrophages) and graft injury were evaluated by histology and immunohistochemistry, and levels of lactat dehydrogenase (LDH) (apoptosis assay), enzyme linked immunosorbent assay for nuclear protein high-mobility-group-protein B1 (HMGB1), tumor necrosis factor alpha (TNF-α) and transforming growth factor beta1 (TGF-β1) in plasma were analysed. RESULTS Clodronate liposomes successfully reduced 70% of M from donor lungs when compared with grafts treated with empty liposome only. M-depleted transplants showed improved histology and revealed considerably less graft damage when compared with control recipients (LDH, P = 0.03; HMGB1, P = 0.3). Oxygenation capacity was ameliorated in M-depleted transplants, if not significant (P = 0.114); however, wet/dry ratio did not differ between groups (P = 0.629). The inflammatory response was significantly reduced in M-depleted mice when compared with control recipients (TNF-α, P = 0.042; TGF-β1, P = 0.039). CONCLUSIONS The selective depletion of M in donor lung transplants can be successfully performed and results in a sustained anti-inflammatory response upon I/R-injury. The beneficial effect of this preconditioning method should be further evaluated as a promising tool for the attenuation of I/R prior to graft implantation in clinical T

An Assessment by In Situ Hybridization Method for Pathogens of Severe Respiratory Infection

It has been shown that the in situ hybridization (ISH)method for the detection of phagocyted bacteria in polymorphonuclear neutrophils is more sensitive than conventional blood culture in patients with sepsis.The present study was designed to further evaluate the clinical utility of the ISH method, using a commercially available kit (Hybrizep(R)), for detecting pathogens in patients with severe respiratory infections. Peripheral blood was taken from patients with severe respiratory infections for both routine blood culture and the ISH method,respectively.In addition,focal samples including sputum,bronchoalveolar lavage,central and thoracic catheter, etc. were simultaneously examined for bacterial culture. A total number of 22 specimens was examined.The positive cases by ISH were 50.0% in the respiratory infections,which were significantly higher than those in blood cultures (9.1%).However, identical pathogens in the ISH method were not isolated from blood and/or other sources in respiratory sites. These findings suggest a possibility of high frequency of bacteremia or multifactorious pathogens in severe respiratory infections.The ISH method may provide additional information on serious respiratory infections for the detection of bacteremia. However, the clinical utility by the ISH method for patients with severe respiratory infection remains undetermined. Shinshu Med J 59 : 223―228, 2011Article信州医学雑誌 59(4): 223-228(2011)departmental bulletin pape

High Resolution Continuous Flow Analysis System developed at the Ice Core Research Center National Institute of Polar Research

第6回極域科学シンポジウム[OM] 極域気水圏11月16日（月）　統計数理研究所 セミナー室2（D304