星川 康

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.

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.

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.

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.

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.

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.

亜急性の低酸素曝露が肺胞上皮のイオントランスポートに及ぼす影響を調べるために, 我々はラット摘出肺の気道をアルブミン液で満たし, 肺胞水分クリアランスを測定した. 先ず, 肺胞水分クリアランスは肺灌流を行わなくともインキュベーション2時間にわたり直線的に上昇すること, その機序が能動的Na⁺イオン輸送に依存していることを明らかにした. 次いでこのモデルを適用し, 48時間の低酸素曝露 (FiO₂=0.1) が肺胞水分クリアランスを減少させることを見いだした. 対照群では肺胞水分クリアランスはアミロライド (Na⁺チャネルプロッカー) やウアバイン (Na⁺-K⁺-ATPase インヒビター) の存在下で有意に抑制されたが, 低酸素曝露肺ではこれらの抑制効果は認められなかった. このことは低酸素曝露による肺胞水分クリアランスの減少にはこれらNa⁺イオンの通過経路にあたる細胞膜蛋白の機能低下が関与していることを示している.

亜急性の低酸素曝露が肺胞上皮のイオントランスポートに及ぼす影響を調べるために, 我々はラット摘出肺の気道をアルブミン液で満たし, 肺胞水分クリアランスを測定した. 先ず, 肺胞水分クリアランスは肺灌流を行わなくともインキュベーション2時間にわたり直線的に上昇すること, その機序が能動的Na⁺イオン輸送に依存していることを明らかにした. 次いでこのモデルを適用し, 48時間の低酸素曝露 (FiO₂=0.1) が肺胞水分クリアランスを減少させることを見いだした. 対照群では肺胞水分クリアランスはアミロライド (Na⁺チャネルプロッカー) やウアバイン (Na⁺-K⁺-ATPase インヒビター) の存在下で有意に抑制されたが, 低酸素曝露肺ではこれらの抑制効果は認められなかった. このことは低酸素曝露による肺胞水分クリアランスの減少にはこれらNa⁺イオンの通過経路にあたる細胞膜蛋白の機能低下が関与していることを示している.

モノクロタリン (Monocrotaline; MCT) による肺高血圧, 肺血管再構築に対するプロスタグランディンE₁ (PGE₁) の効果について検討した. コントロール群 [平均肺動脈圧 (mPAP): 17.2±1.1mmHg, 右室壁重量/左室+中隔重量比 (RV/LV+S): 0.259±0.008] に比し, MCT投与ラット (80mg/kg BW, 1回皮下注) では, 3週間後には肺高血圧 (mPAP: 24.9±1.3mmHg), 右室肥大 (RV/LV+S: 0.327+0.012), および肺動脈中膜肥厚が招来された. PGE₁ (300μg/kg BW) を1日2回皮下投与したラットでは, MCTによる肺高血圧, 右室肥大は有意に抑制された (mPAP: 18.7±0.9mmHg, RV/LV+S: 0.267±0.011). また, PGE₁のRV/LV+S比, 肺動脈中膜肥厚の抑制効果には容量依存性が認められた. 以上より, MCTによる肺高血圧, 右室肥大, 肺動脈中膜肥厚に対するPGE₁の有効性が示唆された.

モノクロタリン (Monocrotaline; MCT) による肺高血圧, 肺血管再構築に対するプロスタグランディンE₁ (PGE₁) の効果について検討した. コントロール群 [平均肺動脈圧 (mPAP): 17.2±1.1mmHg, 右室壁重量/左室+中隔重量比 (RV/LV+S): 0.259±0.008] に比し, MCT投与ラット (80mg/kg BW, 1回皮下注) では, 3週間後には肺高血圧 (mPAP: 24.9±1.3mmHg), 右室肥大 (RV/LV+S: 0.327+0.012), および肺動脈中膜肥厚が招来された. PGE₁ (300μg/kg BW) を1日2回皮下投与したラットでは, MCTによる肺高血圧, 右室肥大は有意に抑制された (mPAP: 18.7±0.9mmHg, RV/LV+S: 0.267±0.011). また, PGE₁のRV/LV+S比, 肺動脈中膜肥厚の抑制効果には容量依存性が認められた. 以上より, MCTによる肺高血圧, 右室肥大, 肺動脈中膜肥厚に対するPGE₁の有効性が示唆された.

Levels of the granulocyte colony-stimulating factor (G-CSF) were determined in the plasma and resected lung tissue from patients who underwent pulmonary resection. Moreover, the effect of recombinant human (rh) G-CSF on the permeability of pulmonary endothelium and on liquid clearance from the alveolar spaces was investigated in rabbits. The plasma levels of G-CSF increased from 30 pg/ml preoperatively to 409 ± 236 pg/ml 3 h postoperatively (P &lt 0.05), while the levels of G-CSF in the resected lung tissue were increased in the alveolar fluid, to 1,834 ± 1,054 pg/ml, and in the pulmonary blood, to 5,466 ± 2,019 pg/ml. It was found that rh G-CSF 25 μg administered into the subcutaneous tissue of rabbits increased extravascular lung water to 3.45 ± 0.26 vs 2.98 ± 0.20 in control experiments (P &lt 0.05) however, rhG-CSF 0.75 pg/kg administered into the alveloar spaces did not affect liquid clearance from the alveolar spaces. The findings of this study led us to conclude that G-CSF is synthesized in the human lung and increases the permeability of pulmonary endothelium, but not liquid clearance across the alveolar epithelium. © 1994 Springer-Verlag.

Levels of the granulocyte colony-stimulating factor (G-CSF) were determined in the plasma and resected lung tissue from patients who underwent pulmonary resection. Moreover, the effect of recombinant human (rh) G-CSF on the permeability of pulmonary endothelium and on liquid clearance from the alveolar spaces was investigated in rabbits. The plasma levels of G-CSF increased from 30 pg/ml preoperatively to 409 +/- 236 pg/ml 3 h postoperatively (P < 0.05), while the levels of G-CSF in the resected lung tissue were increased in the alveolar fluid, to 1,834 +/- 1,054 pg/ml, and in the pulmonary blood, to 5,466 +/- 2,019 pg/ml. It was found that rh G-CSF 25 mu g administered into the subcutaneous tissue of rabbits increased extravascular lung water to 3.45 +/- 0.26 vs 2.98 +/- 0.20 in control experiments (P < 0.05); however, rhG-CSF 0.75 mu g/kg administered into the alveloar spaces did not affect liquid clearance from the alveolar spaces. The findings of this study led us to conclude that G-CSF is synthesized in the human lung and increases the permeability of pulmonary endothelium, but not liquid clearance across the alveolar epithelium.

肺切除術後の右心不全等の心合併症の発生と術前一側肺動脈閉塞試験時の右室駆出率の変化との関連について検討した. 基礎心疾患のない肺切除予定の患者 (n=34) に一側肺動脈閉塞試験を施行し, 閉塞前と閉塞中の右室駆出率, 右室拡張末期容量, 及び収縮末期容量, 全肺血管抵抗を測定した. このデーターと術後心合併症の有無との関連について検討した. 閉塞試験による全肺血管抵抗の変化率に拘わらず右室拡張末期容量の変化率が120%以上になる例が6例あり, これらは術後にジギタリス, カテコールアミンあるいは抗不整脈剤の投与を必要とする血圧低下, 又は, 不整脈を合併した. このことより一側肺動脈閉塞試験時の右室拡張末期容量の変化率と肺切除術後の心合併症との関連性が示唆された.

肺切除術後の右心不全等の心合併症の発生と術前一側肺動脈閉塞試験時の右室駆出率の変化との関連について検討した. 基礎心疾患のない肺切除予定の患者 (n=34) に一側肺動脈閉塞試験を施行し, 閉塞前と閉塞中の右室駆出率, 右室拡張末期容量, 及び収縮末期容量, 全肺血管抵抗を測定した. このデーターと術後心合併症の有無との関連について検討した. 閉塞試験による全肺血管抵抗の変化率に拘わらず右室拡張末期容量の変化率が120%以上になる例が6例あり, これらは術後にジギタリス, カテコールアミンあるいは抗不整脈剤の投与を必要とする血圧低下, 又は, 不整脈を合併した. このことより一側肺動脈閉塞試験時の右室拡張末期容量の変化率と肺切除術後の心合併症との関連性が示唆された.