ROLE OF ADHESION MOLECULES IN PATHOPHYSIOLOGY OF RESPIRATORY DISEASES AND DEVELOPMENT OF NEW THERAPEUTICAL METHODS.

粘附分子在呼吸系统疾病病理生理学中的作用和新治疗方法的开发。

• 批准号: 05454254
• 负责人: KITAMURA Satoshi
• 金额: $ 4.16万
• 依托单位: JICHI MEDICAL SCHOOL
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454254/
• 关键词: ADHESION MOLECULES; ACUTE LUNG INJURY; CD18; ICAM-1; VASCULAR ENDOTHELIAL CELL; LEUKOCYTE; CYTOKINES; 接着分子; ICAM-1; CD18; エンドトキシン; 接着阻害療法; 好中球; ARDS; 急性肺損傷; びまん性肺疾患; サルコイドーシス; 放射線肺臓炎

Neutrophils (PMN) are important effector cells in the pathophysiology of acute lung injury. By various stimuli, circulating neutrophils adhere to vascular endothelial cells and transmigrate to the interstitium. In these steps, PMN are activated and release reactive oxygen species (ROI) and proteases, which cause increase in endothelial permeability and tissue injury. Adhesion molecules play a central role in these neutrophil-mediated mechanisms of lung injury. Using an endothelial monolayr system for in vitro permeability assay, we examined whether the increase in vascular endothelial permeability is dependent on adhesion of PMN to endothelial cells via ahdesion molecules (through the CD18 integrin on PMN and ICAM-1 on the endothelium) and it is mediated by the toxic mediators, such as hydrogen peroxide and neutrophil elastase, released from PMN.Lechitinized-SOD and elastase inhibitors (ONO-5046 and urinastatin) decreased PMA-stimulated PMN-mediated increase in endothelial permeability … More . The inhibition of PMN adhesion to endothelial cells using an anti-CD18 mAb or an anti-adhesion agent, leumedin, also blocked the PMN-mediated increase in endothelial permeability. Theses findings indicated that the adhesion event is critical in mediating the PMN-dependent increase in vascular endothelial permeability. We also examined the effect of transmigration of PMN on endothelial barrier function. PMN-migration through endothelial monolayrs induced by the concentration gradient of IL-8 did not increase the endothelial permeability by itself, but it did increase the permeability when endothelial monolayr was pretreated with low concentration of TNFa. This effect of TNFa was inhibited by an anti-CD18 mAb.Recently, it has been reported that reactive oxygen intermediates (ROI), such as hydrogen peroxide, play an important role in the pathophysiology of acute lung injury not only as a terminal effector, but also as a second messenger of signal transduction pathway. We investigated the role of ROI in the mechanism of adhesion molecule expression. N-acetylcysteine (NAC), an antioxidant, decreased the TNFa-induced expression of intercellular adhesion molecule-1 (ICAM-1) on the cultured human bronchial epithelial cells (BEAS-2B). NAC also attenuated the intratracheal LPS-induced PMN sequestration and ICAM-1 expression in rat lungs. These findings suggest that adhesion molecule expression in lung is mediated by the production of ROI.NF-kB activation may be involved in this pathway.Since adhesion molecules play a crucial role in the pathophysiology of neutrophil-mediated acute lung injury, the inhibition of adhesion using anti-oxidants like NAC as well as monoclonal antibodies against adhesion molecules may be useful therapeutic agents. Less

中性粒细胞（PMN）是急性肺损伤病理生理学中重要的效应细胞。通过各种刺激，循环中性粒细胞粘附于血管内皮细胞并迁移至间质。在这些步骤中，PMN 被激活并释放活性氧 (ROI) 和蛋白酶，从而导致内皮通透性增加和组织损伤。粘附分子在中性粒细胞介导的肺损伤机制中发挥着核心作用。使用内皮单层系统进行体外通透性测定，我们检查了血管内皮通透性的增加是否依赖于中性粒细胞通过粘附分子（通过中性粒细胞上的 CD18 整联蛋白和内皮上的 ICAM-1）与内皮细胞的粘附，并且它是由中性粒细胞释放的有毒介质（例如过氧化氢和中性粒细胞弹性蛋白酶）介导的。 PMN.卵磷脂化 SOD 和弹性蛋白酶抑制剂（ONO-5046 和 urinastatin）降低了 PMA 刺激的 PMN 介导的内皮通透性增加……更多。使用抗 CD18 mAb 或抗粘附剂亮美素抑制 PMN 与内皮细胞的粘附，也阻止了 PMN 介导的内皮通透性增加。这些发现表明，粘附事件对于介导 PMN 依赖性血管内皮通透性增加至关重要。我们还研究了中性粒细胞迁移对内皮屏障功能的影响。 IL-8浓度梯度诱导的PMN通过内皮单层的迁移本身并不增加内皮通透性，但当用低浓度的TNFa预处理内皮单层时，它确实增加了通透性。 TNFa的这种作用可被抗CD18单克隆抗体抑制。最近有报道称，过氧化氢等活性氧中间体（ROI）在急性肺损伤的病理生理学中发挥着重要作用，不仅作为终末效应物，而且作为信号转导途径的第二信使。我们研究了 ROI 在粘附分子表达机制中的作用。 N-乙酰半胱氨酸 (NAC) 是一种抗氧化剂，可降低培养的人支气管上皮细胞 (BEAS-2B) 上 TNFa 诱导的细胞间粘附分子-1 (ICAM-1) 的表达。 NAC 还减弱气管内 LPS 诱导的 PMN 隔离和大鼠肺部 ICAM-1 表达。这些发现表明，肺中粘附分子的表达是由 ROI 的产生介导的。NF-kB 激活可能参与了该途径。由于粘附分子在中性粒细胞介导的急性肺损伤的病理生理学中发挥着至关重要的作用，因此使用 NAC 等抗氧化剂以及针对粘附分子的单克隆抗体来抑制粘附可能是有用的 治疗剂。较少的

项目成果

Kitamura, S.: "Role of adhesion molecules in Acute lung injury" nanoGIGA. 3. 75-80 (1994)

Kitamura, S.：“粘附分子在急性肺损伤中的作用”nanoGIGA。

北村 諭: "ショックの病態に接着分子はどのように関与しているか-acutelung injuryを中心" 日本ショック学会雑誌. 9(2). (1994)

Satoshi Kitamura：“粘附分子如何参与休克的病理学 - 关注急性肺损伤”，日本休克研究学会杂志 9（2）。

石井芳樹: "びまん性間質性肺疾患と接着分子" 医学のあゆみ. 168. 659-664 (1994)

Yoshiki Ishii：“弥漫性间质性肺疾病和粘附分子”医学史 168. 659-664 (1994)。

石井芳樹: "急性肺損傷における接着分子の役割" 集中治療. 6. 1043-1054 (1994)

Yoshiki Ishii：“粘附分子在急性肺损伤中的作用”重症监护 6. 1043-1054 (1994)。

Ishii,Y.,and Kitamura,S.: "Elevated Levels of Soluble ICAM-I in Serum and Bronchoalveolar Lavage Fluid in Active Sarcoidosis." Chest. (in press).

Ishii,Y. 和 Kitamura,S.：“活动性结节病血清和支气管肺泡灌洗液中可溶性 ICAM-I 水平升高。”