星川 康

Objectives. 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11beta-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11beta-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation. Design. Controlled laboratory study. Setting., University research laboratory. Subjects. Adult Sprague-Dawley rats (n = 66). Interventions., Rats were intraperitoneally injected with carbenoxolone (2 x 10 mg(.)kg(-1.)day(-1) for 3 days) and allowed free access to water and food. Rats were further challenged with endotoxin instillation (1 mg/kg). Measurements and Main Results: We discovered that carbenoxolone significantly increased messenger RNA expression of all three epithelial sodium channel subunits in distal lung tissues (two-fold increase of alpha-subunit, four-fold increase of beta-subunit, and two-fold increase of gamma-subunit) as well as in trachea. Carbenoxolone increased the amiloride-sensitive alveolar fluid clearance significantly. When rats were further challenged by endotoxin instillation (1 mg/kg), pretreatment with carbenoxolone significantly inhibited endotoxin-induced increase in lung neutrophils as well as tumor necrosis factor-a and cytokine-induced neutrophil chemoattractant-1 concentrations in serum and bronchoalveolar lavage fluid. Conclusions: These beneficial effects of carbenoxolone on lung fluid balance and inflammation are very similar to those expected when glucocorticoids are introduced exogenously. We conclude that carbenoxolone increased the actions of endogenous bioactive glucocorticoids on lung cells by reducing local steroid breakdown.

Objectives. 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11beta-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11beta-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation. Design. Controlled laboratory study. Setting., University research laboratory. Subjects. Adult Sprague-Dawley rats (n = 66). Interventions., Rats were intraperitoneally injected with carbenoxolone (2 x 10 mg(.)kg(-1.)day(-1) for 3 days) and allowed free access to water and food. Rats were further challenged with endotoxin instillation (1 mg/kg). Measurements and Main Results: We discovered that carbenoxolone significantly increased messenger RNA expression of all three epithelial sodium channel subunits in distal lung tissues (two-fold increase of alpha-subunit, four-fold increase of beta-subunit, and two-fold increase of gamma-subunit) as well as in trachea. Carbenoxolone increased the amiloride-sensitive alveolar fluid clearance significantly. When rats were further challenged by endotoxin instillation (1 mg/kg), pretreatment with carbenoxolone significantly inhibited endotoxin-induced increase in lung neutrophils as well as tumor necrosis factor-a and cytokine-induced neutrophil chemoattractant-1 concentrations in serum and bronchoalveolar lavage fluid. Conclusions: These beneficial effects of carbenoxolone on lung fluid balance and inflammation are very similar to those expected when glucocorticoids are introduced exogenously. We conclude that carbenoxolone increased the actions of endogenous bioactive glucocorticoids on lung cells by reducing local steroid breakdown.

Background. Cold preservation is the most practical method to maintain the viability of isolated lungs. However, rapid cooling may affect pulmonary endothelial function. We examined the effects of microtubule stabilization with paclitaxel on pulmonary endothelial barrier integrity under cold temperature. Methods. Human pulmonary arterial endothelial cells were incubated at VC for 2 hr in the presence or absence of paclitaxel (2.5 mumol/L). Microtubules was visualized using immunocytochemical techniques. Ultrasonic attenuation was measured with scanning acoustic microscopy. Endothelial barrier integrity was measured as transendothelial electric resistance. In addition, we examined graft function in a rat lung transplantation model, in which the donor lung had been preserved in the presence of paclitaxel (2.5 mumol/L) at 4degreesC for 12 hr. Results. Low temperature caused a reversible microtubule disassembly, but the structure of microtubules was preserved by paclitaxel. Paclitaxel prevented the cooling-induced decrease in ultrasonic attenuation and transendothelial electric resistance. In a rat transplantation model, we found that preservation with paclitaxel successfully improved the oxygenation performance of the donor lung, which demonstrated only mild congestion and less significant interstitial edema without fluid accumulation in the alveolar spaces. Conclusions. Our results indicate that microtubule stabilization with paclitaxel maybe beneficial to prevent the loss of the endothelial barrier during cold preservation. We conclude that the use of paclitaxel in organ preservation solutions is useful in protecting pulmonary endothelial barrier integrity during cold preservation, thereby reducing the occurrence of early graft failure.

Background. Cold preservation is the most practical method to maintain the viability of isolated lungs. However, rapid cooling may affect pulmonary endothelial function. We examined the effects of microtubule stabilization with paclitaxel on pulmonary endothelial barrier integrity under cold temperature. Methods. Human pulmonary arterial endothelial cells were incubated at VC for 2 hr in the presence or absence of paclitaxel (2.5 mumol/L). Microtubules was visualized using immunocytochemical techniques. Ultrasonic attenuation was measured with scanning acoustic microscopy. Endothelial barrier integrity was measured as transendothelial electric resistance. In addition, we examined graft function in a rat lung transplantation model, in which the donor lung had been preserved in the presence of paclitaxel (2.5 mumol/L) at 4degreesC for 12 hr. Results. Low temperature caused a reversible microtubule disassembly, but the structure of microtubules was preserved by paclitaxel. Paclitaxel prevented the cooling-induced decrease in ultrasonic attenuation and transendothelial electric resistance. In a rat transplantation model, we found that preservation with paclitaxel successfully improved the oxygenation performance of the donor lung, which demonstrated only mild congestion and less significant interstitial edema without fluid accumulation in the alveolar spaces. Conclusions. Our results indicate that microtubule stabilization with paclitaxel maybe beneficial to prevent the loss of the endothelial barrier during cold preservation. We conclude that the use of paclitaxel in organ preservation solutions is useful in protecting pulmonary endothelial barrier integrity during cold preservation, thereby reducing the occurrence of early graft failure.

Background: The interaction between neutrophils and platelets may be important in the modulation of pulmonary haemodynamics under systemic inflammatory conditions. A study was undertaken to examine whether antiplatelet agents inhibit platelet-neutrophil adherence and ameliorate the pulmonary haemodynamic response to fMLP by inhibiting thromboxane release in endotoxin primed lungs. fMLP stimulates neutrophils but not platelets; however, thromboxane synthesis in neutrophils is very low. Methods: Rats were pretreated with either cilostazol (300 mg/kg) or aspirin (50 mg/kg) before endotoxin priming (5 mg/kg). Platelets in the lung were identified by fluorescent immunohistochemistry. Platelet-neutrophil adherence was analysed by flow cytometry of the lung vascular flush. The effect of fMLP (10 26 M) on thromboxane release, lung weight (an indicator of pulmonary vasoconstriction), and lung filtration coefficient was determined in an isolated lung system perfused at a constant pressure difference. Results: Endotoxin induced platelet accumulation and platelet-neutrophil adherence in the lung capillary were completely inhibited by cilostazol and aspirin while neutrophil recruitment was not affected. The fMLP challenge caused a significant increase in thromboxane B-2 levels in endotoxin primed lungs. The fMLP induced decrease in lung weight was enhanced by endotoxin priming (from -4.9 to -63.9 mg, 95% CI of mean difference -99.5 to -10.5 mg, p < 0.05). The fMLP induced increase in the lung filtration coefficient was also enhanced by endotoxin priming (from 0.63 to 2.40 mg/min/cm H2O/g, 95% CI of mean difference 1.17 to 2.37 mg/min/cm H2O/g, p, 0.05). Treatment with cilostazol and aspirin completely inhibited the enhanced pulmonary haemodynamic response to fMLP. Conclusion: The neutrophil-platelet interaction is of critical importance in the modulation of pulmonary haemodynamics via thromboxane.

症例は29歳, 男性. トラック運転中に居眠りをして大型トラックに追突, ハンドルで前胸部を強打した. 近医に搬送され気管分岐部裂傷の診断を得て, 当科に紹介された.気管支鏡検査上, 気管分岐部竜骨の左右主気管支接合部が損傷し直径約8mmの裂孔が認められた.受傷約24時間後に手術を開始.竜骨の損傷が比較的広範なため, 明らかな損傷部のみのdebridementと単純縫合閉鎖では術後縫合不全や肉芽性狭窄の危険性が高いと考え, 気管分岐部を切除しMontage型再建術を行った.術後, 気管・気管支吻合部合併症をきたすことなく良好に経過し第29病日に退院した.気管分岐部損傷に対する分岐部切除再建術の報告はこれまでないが, 竜骨の広範な破壊を伴う症例に対しては, 積極的にこの術式を考慮してよいと考える.

Background: The interaction between neutrophils and platelets may be important in the modulation of pulmonary haemodynamics under systemic inflammatory conditions. A study was undertaken to examine whether antiplatelet agents inhibit platelet-neutrophil adherence and ameliorate the pulmonary haemodynamic response to fMLP by inhibiting thromboxane release in endotoxin primed lungs. fMLP stimulates neutrophils but not platelets; however, thromboxane synthesis in neutrophils is very low. Methods: Rats were pretreated with either cilostazol (300 mg/kg) or aspirin (50 mg/kg) before endotoxin priming (5 mg/kg). Platelets in the lung were identified by fluorescent immunohistochemistry. Platelet-neutrophil adherence was analysed by flow cytometry of the lung vascular flush. The effect of fMLP (10 26 M) on thromboxane release, lung weight (an indicator of pulmonary vasoconstriction), and lung filtration coefficient was determined in an isolated lung system perfused at a constant pressure difference. Results: Endotoxin induced platelet accumulation and platelet-neutrophil adherence in the lung capillary were completely inhibited by cilostazol and aspirin while neutrophil recruitment was not affected. The fMLP challenge caused a significant increase in thromboxane B-2 levels in endotoxin primed lungs. The fMLP induced decrease in lung weight was enhanced by endotoxin priming (from -4.9 to -63.9 mg, 95% CI of mean difference -99.5 to -10.5 mg, p < 0.05). The fMLP induced increase in the lung filtration coefficient was also enhanced by endotoxin priming (from 0.63 to 2.40 mg/min/cm H2O/g, 95% CI of mean difference 1.17 to 2.37 mg/min/cm H2O/g, p, 0.05). Treatment with cilostazol and aspirin completely inhibited the enhanced pulmonary haemodynamic response to fMLP. Conclusion: The neutrophil-platelet interaction is of critical importance in the modulation of pulmonary haemodynamics via thromboxane.

症例は29歳, 男性. トラック運転中に居眠りをして大型トラックに追突, ハンドルで前胸部を強打した. 近医に搬送され気管分岐部裂傷の診断を得て, 当科に紹介された.気管支鏡検査上, 気管分岐部竜骨の左右主気管支接合部が損傷し直径約8mmの裂孔が認められた.受傷約24時間後に手術を開始.竜骨の損傷が比較的広範なため, 明らかな損傷部のみのdebridementと単純縫合閉鎖では術後縫合不全や肉芽性狭窄の危険性が高いと考え, 気管分岐部を切除しMontage型再建術を行った.術後, 気管・気管支吻合部合併症をきたすことなく良好に経過し第29病日に退院した.気管分岐部損傷に対する分岐部切除再建術の報告はこれまでないが, 竜骨の広範な破壊を伴う症例に対しては, 積極的にこの術式を考慮してよいと考える.

A case of primary mucinous cystadenocarcinoma of the lung is presented. The patient was a 42-year-old woman with a 5-cm left lung mass. Left lower lobectomy was performed and analysis of a frozen section revealed mucinous cystadenocarcinoma. The tumor was a fibrous, walled cyst containing abundant mucinous material. Sparse groups of malignant cells were microscopically observed in pools of mucin; thus, the tumor resembled mucinous cystadenocarcinoma that occurs in the ovary, appendix, or pancreas. The tumor we found is a very rare intrapulmonary neoplasm that is differentiated from a metastatic lesion and mucinous bronchoalveolar carcinoma by its very different clinical course and prognosis. (C) 2003 by The Society of Thoracic Surgeons.

A case of primary mucinous cystadenocarcinoma of the lung is presented. The patient was a 42-year-old woman with a 5-cm left lung mass. Left lower lobectomy was performed and analysis of a frozen section revealed mucinous cystadenocarcinoma. The tumor was a fibrous, walled cyst containing abundant mucinous material. Sparse groups of malignant cells were microscopically observed in pools of mucin; thus, the tumor resembled mucinous cystadenocarcinoma that occurs in the ovary, appendix, or pancreas. The tumor we found is a very rare intrapulmonary neoplasm that is differentiated from a metastatic lesion and mucinous bronchoalveolar carcinoma by its very different clinical course and prognosis. (C) 2003 by The Society of Thoracic Surgeons.

Different animal species have a varying response to hypoxia. Mice develop less pulmonary artery thickening after chronic hypoxia exposure than rats. We hypothesized that the lung tissue gene expression pattern displayed in hypoxic rats would differ from that of hypoxic mice. We exposed Sprague-Dawley rats and C57BL/6 mice to both 1 and 3 wk of hypobaric hypoxia. Although both species developed pulmonary hypertension, mice showed less pulmonary vascular remodeling than rats. Microarray gene analysis demonstrated a distinct pattern of gene expression between mice and rats when exposed to hypoxic conditions. In addition, some genes appeared to be more responsive at an earlier time point of 1 wk of hypoxia. Hypoxic conditions in the rat induce genes involved in endothelial cell proliferation, repression of apoptosis, and vasodilation. Mice exposed to hypoxic conditions decrease the expression of genes involved in vasodilation and in endothelial cell proliferation. Although we cannot determine whether the differential expression of genes during chronic hypoxia is cause or consequence of the differential pulmonary vascular remodeling, we propose that a balance between over- and under-expression of a selective group of genes may be responsible for lung vascular remodeling and vascular tone control.

Different animal species have a varying response to hypoxia. Mice develop less pulmonary artery thickening after chronic hypoxia exposure than rats. We hypothesized that the lung tissue gene expression pattern displayed in hypoxic rats would differ from that of hypoxic mice. We exposed Sprague-Dawley rats and C57BL/6 mice to both 1 and 3 wk of hypobaric hypoxia. Although both species developed pulmonary hypertension, mice showed less pulmonary vascular remodeling than rats. Microarray gene analysis demonstrated a distinct pattern of gene expression between mice and rats when exposed to hypoxic conditions. In addition, some genes appeared to be more responsive at an earlier time point of 1 wk of hypoxia. Hypoxic conditions in the rat induce genes involved in endothelial cell proliferation, repression of apoptosis, and vasodilation. Mice exposed to hypoxic conditions decrease the expression of genes involved in vasodilation and in endothelial cell proliferation. Although we cannot determine whether the differential expression of genes during chronic hypoxia is cause or consequence of the differential pulmonary vascular remodeling, we propose that a balance between over- and under-expression of a selective group of genes may be responsible for lung vascular remodeling and vascular tone control.

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I-2 (PGI(2) prostacyclin) is a PGH(2) metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI(2) has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF(1alpha), not a decrease in PGE(2). Thus, elevated PGI(2) levels and not decreased PGE(2) levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer.

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I-2 (PGI(2) prostacyclin) is a PGH(2) metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI(2) has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF(1alpha), not a decrease in PGE(2). Thus, elevated PGI(2) levels and not decreased PGE(2) levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer.

Prostacyclin (PGI(2)) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI(2) receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI(2) and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

Prostacyclin (PGI(2)) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI(2) receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI(2) and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days I and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21 especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.

Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days I and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21 especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.

Background. The number of patients with lung cancer is increasing. This study was undertaken to realize the probability, fate and management of acute fatal postoperative complications, Since interstitial pneumonia was one of the most fatal postoperative complications, to know its incidence and fate is very important. Methods. A total of 2667 patients who underwent thoracotomy caused by malignant tumors during the past 17 years were reviewed and studied. We performed investigations on medical records, chest X-rays, whole-body CT films, operative records and pathological specimens for all inpatients Results. Nineteen patients died in hospital 30 days after thoracotomy (operative death). Nine patients died in hospital more than 31 days after thoracotomy (hospital death). Eight cases out of 28 patients (operative and hospital deaths) developed and finally died by interstitial pneumonia, Each case was treated with steroids, neutrophil-elastase inhibitor, and/or immunosuppressive agents. These patients could not be selected by any preoperative laboratory examination, such as preoperative pulmonary function tests, serum biochemistry tests, and chest X-ray or CT films, Interstitial pneumonia as a complication of postoperative stage, was fatal and once developed, it was very difficult to save their lives. Conclusions. Since we reported the cases who died from acute postoperative complications, especially interstitial pneumonia, we could not present effective management. However, in this report, several therapeutic trials that may solve the problems of acute postoperative interstitial pneumonia were proposed.

Background. The number of patients with lung cancer is increasing. This study was undertaken to realize the probability, fate and management of acute fatal postoperative complications, Since interstitial pneumonia was one of the most fatal postoperative complications, to know its incidence and fate is very important. Methods. A total of 2667 patients who underwent thoracotomy caused by malignant tumors during the past 17 years were reviewed and studied. We performed investigations on medical records, chest X-rays, whole-body CT films, operative records and pathological specimens for all inpatients Results. Nineteen patients died in hospital 30 days after thoracotomy (operative death). Nine patients died in hospital more than 31 days after thoracotomy (hospital death). Eight cases out of 28 patients (operative and hospital deaths) developed and finally died by interstitial pneumonia, Each case was treated with steroids, neutrophil-elastase inhibitor, and/or immunosuppressive agents. These patients could not be selected by any preoperative laboratory examination, such as preoperative pulmonary function tests, serum biochemistry tests, and chest X-ray or CT films, Interstitial pneumonia as a complication of postoperative stage, was fatal and once developed, it was very difficult to save their lives. Conclusions. Since we reported the cases who died from acute postoperative complications, especially interstitial pneumonia, we could not present effective management. However, in this report, several therapeutic trials that may solve the problems of acute postoperative interstitial pneumonia were proposed.

Background. The mechanism by which stimulated neutrophils (polymorphonuclear leukocytes [PMNs]) damage pulmonary vascular endothelium was investigated. Methods. The ability of unstimulated and mechanically stimulated PMNs to adhere to pulmonary endothelial cells and, thereby, alter pulmonary vascular permeability was tested. Each series was conducted an 6 rats. To stimulate PMNs, they were agitated gently in a glass vial for 10 seconds. Results. Perfusing lungs with the stimulated PMNs elicited a fivefold increase in permeability compared with lungs perfused with the unstimulated cells. This increase in permeability was blocked completely by preincubation of stimulated PMNs with CD18 monoclonal antibody. This increase in permeability was also blocked completely by superoxide dismutase (SOD) or the xanthine oxidase (XO) inhibitor allopurinol. Pulmonary vascular hemodynamics were unaffected by any treatment protocol. The accumulation of stimulated PMNs within the lungs was not inhibited by SOD but was partially blocked by allopurinol. Conclusions. These findings suggest that stimulated PR IN-induced increases in pulmonary vascular filtration resulted from endothelial cell injury caused by superoxide anion possibly generated by XO, exclusively present in the endothelial cells. (C) 2000 by The Society of Thoracic Surgeons.

Background. The mechanism by which stimulated neutrophils (polymorphonuclear leukocytes [PMNs]) damage pulmonary vascular endothelium was investigated. Methods. The ability of unstimulated and mechanically stimulated PMNs to adhere to pulmonary endothelial cells and, thereby, alter pulmonary vascular permeability was tested. Each series was conducted an 6 rats. To stimulate PMNs, they were agitated gently in a glass vial for 10 seconds. Results. Perfusing lungs with the stimulated PMNs elicited a fivefold increase in permeability compared with lungs perfused with the unstimulated cells. This increase in permeability was blocked completely by preincubation of stimulated PMNs with CD18 monoclonal antibody. This increase in permeability was also blocked completely by superoxide dismutase (SOD) or the xanthine oxidase (XO) inhibitor allopurinol. Pulmonary vascular hemodynamics were unaffected by any treatment protocol. The accumulation of stimulated PMNs within the lungs was not inhibited by SOD but was partially blocked by allopurinol. Conclusions. These findings suggest that stimulated PR IN-induced increases in pulmonary vascular filtration resulted from endothelial cell injury caused by superoxide anion possibly generated by XO, exclusively present in the endothelial cells. (C) 2000 by The Society of Thoracic Surgeons.

原発性肺癌2,632例の中で非治癒切除は578例 (22%) であったが, その内5年以上生存した56例 (9.7%) (A群) の臨床病理学的特徴を検討した.さらに, 非治癒切除に終わった全578症例 (B群) と比較した.5年以上生存した絶非治切18例の診断根拠は, 気管支断端陽性9例, 悪性胸水5例, 胸膜播種2例, 癌遺残2例で, 重複を認めなかった.5年以上生存した相非治切38例の診断根拠は, 肺葉切除かつR1郭清9例, 部分区域切除もしくは肺葉切除かつRO郭清21例, R2b郭清かつ第2b群リンパ節転移陽性8例であった.合併切除部位は, 心膜・胸壁・左房および壁側胸膜であり, 大血管・横隔膜・食道浸潤例はなかった.A群はB群に比較し, T3・T4例およびN2例が少なく, D0症例が多かった.非治癒切除長期生存例の多くは, 非治癒切除例において比較的進行していない症例群であった.相非治切長期生存例の中には, 部切・区域切除もしくはRO・R1郭清で根治できた症例がみられた.

During cardiopulmonary bypass (CPB), neutrophils (PMNs) may be stimulated by shear stress which could contribute to the pulmonary injury that occurs after CPB. To elucidate whether mechanically stimulated PMNs increase pulmonary vascular permeability, measured as the pulmonary filtration coefficient (K) and pulmonary vascular resistance, and to elucidate whether superoxide anion mediates this increase, we assessed the effects of stimulated and unstimulated PMNs, and of superoxide dismutase (SOD) on K and resistance in isolated perfused lungs from Sprague-Dawley rats. PMNs were stimulated by gentle agitation in a glass vial for 10s. Lungs perfused with the stimulated PMNs, being the stimulated group (n = 6), elicited a 5-fold increase in the filtration coefficient compared with lungs perfused with unstimulated cells, being the unstimulated group (n = 6), This increase in filtration was completely blocked by the preincubation of stimulated PMNs with CD18 monoclonal antibody, being the Ab group (n = 6), and also by superoxide dismutase, being the SOD group (n = 6). Pulmonary vascular resistance was not increased by stimulated PMNs, and the accumulation of stimulated PMNs was not blocked by SOD. These findings suggest that stimulated PMNs increase K and that superoxide anion may injure the pulmonary vascular endothelial cells.

原発性肺癌2,632例の中で非治癒切除は578例 (22%) であったが, その内5年以上生存した56例 (9.7%) (A群) の臨床病理学的特徴を検討した.さらに, 非治癒切除に終わった全578症例 (B群) と比較した.5年以上生存した絶非治切18例の診断根拠は, 気管支断端陽性9例, 悪性胸水5例, 胸膜播種2例, 癌遺残2例で, 重複を認めなかった.5年以上生存した相非治切38例の診断根拠は, 肺葉切除かつR1郭清9例, 部分区域切除もしくは肺葉切除かつRO郭清21例, R2b郭清かつ第2b群リンパ節転移陽性8例であった.合併切除部位は, 心膜・胸壁・左房および壁側胸膜であり, 大血管・横隔膜・食道浸潤例はなかった.A群はB群に比較し, T3・T4例およびN2例が少なく, D0症例が多かった.非治癒切除長期生存例の多くは, 非治癒切除例において比較的進行していない症例群であった.相非治切長期生存例の中には, 部切・区域切除もしくはRO・R1郭清で根治できた症例がみられた.

During cardiopulmonary bypass (CPB), neutrophils (PMNs) may be stimulated by shear stress which could contribute to the pulmonary injury that occurs after CPB. To elucidate whether mechanically stimulated PMNs increase pulmonary vascular permeability, measured as the pulmonary filtration coefficient (K) and pulmonary vascular resistance, and to elucidate whether superoxide anion mediates this increase, we assessed the effects of stimulated and unstimulated PMNs, and of superoxide dismutase (SOD) on K and resistance in isolated perfused lungs from Sprague-Dawley rats. PMNs were stimulated by gentle agitation in a glass vial for 10s. Lungs perfused with the stimulated PMNs, being the stimulated group (n = 6), elicited a 5-fold increase in the filtration coefficient compared with lungs perfused with unstimulated cells, being the unstimulated group (n = 6), This increase in filtration was completely blocked by the preincubation of stimulated PMNs with CD18 monoclonal antibody, being the Ab group (n = 6), and also by superoxide dismutase, being the SOD group (n = 6). Pulmonary vascular resistance was not increased by stimulated PMNs, and the accumulation of stimulated PMNs was not blocked by SOD. These findings suggest that stimulated PMNs increase K and that superoxide anion may injure the pulmonary vascular endothelial cells.

To determine whether mechanically stimulated leukocytes increase pulmonary vascular permeability and resistance and, if so, whether cyclooxygenase metabolites mediate the increase, me assessed the effects of stimulated and unstimulated leukocytes, and of a cyclooxygenase inhibitor on pulmonary vascular permeability and resistance in isolated perfused lungs from Sprague-Dawley rats. Leukocytes were stimulated by gentle agitation in a glass container for 10 seconds. After baseline measurements mere made, stimulated or unstimulated leukocytes mere added to the perfusate. The effects of the cyclooxygenase inhibitor, meclofenamate, on the pulmonary vascular filtration coefficient and pulmonary vascular resistance were measured. In the rats that received stimulated leukocytes, the pulmonary vascular filtration coefficient and the vascular resistance were about 2.5 times and 3.3 times higher, respectively, than those in the rats that received unstimulated leukocytes. These increases were completely and partly blocked by meclofenamate. Histological examination indicated that meclofenamate did not prevent the adhesion of leukocytes to the pulmonary vascular endothelium. These findings suggest that mechanically stimulated leukocytes increase pulmonary vascular permeability and that cyclooxygenase metabolites produced by endothelial cells may injure the cells. (C) 1997 Tohoku University Medical Press.

To determine whether mechanically stimulated leukocytes increase pulmonary vascular permeability and resistance and, if so, whether cyclooxygenase metabolites mediate the increase, me assessed the effects of stimulated and unstimulated leukocytes, and of a cyclooxygenase inhibitor on pulmonary vascular permeability and resistance in isolated perfused lungs from Sprague-Dawley rats. Leukocytes were stimulated by gentle agitation in a glass container for 10 seconds. After baseline measurements mere made, stimulated or unstimulated leukocytes mere added to the perfusate. The effects of the cyclooxygenase inhibitor, meclofenamate, on the pulmonary vascular filtration coefficient and pulmonary vascular resistance were measured. In the rats that received stimulated leukocytes, the pulmonary vascular filtration coefficient and the vascular resistance were about 2.5 times and 3.3 times higher, respectively, than those in the rats that received unstimulated leukocytes. These increases were completely and partly blocked by meclofenamate. Histological examination indicated that meclofenamate did not prevent the adhesion of leukocytes to the pulmonary vascular endothelium. These findings suggest that mechanically stimulated leukocytes increase pulmonary vascular permeability and that cyclooxygenase metabolites produced by endothelial cells may injure the cells. (C) 1997 Tohoku University Medical Press.