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的重要效应细胞。通过各种刺激，循环中性粒细胞粘附在血管内皮细胞上并传递到间质。在这些步骤中，PMN被激活并释放活性氧（ROI）和蛋白酶，这会导致内皮通透性和组织损伤的增加。粘附分子在这些中性粒细胞介导的肺损伤机制中起着核心作用。使用内皮单层系统进行体外通透性评估，我们检查了血管内皮内皮渗透性的增加是否取决于PMN通过ADESION分子依从性对内皮细胞的依从性（通过CD18通过CD18整合素对EL的PMN和ICAM-1上的pMN和IT型在内皮中的杂物材料），以及像水中介质的杂物材料，以及像水中的杂物材料一样，例如水分含量） PMN.Lechitinized-SOD和弹性酶抑制剂（ONO-5046和Urinastatin）产生了PMA刺激的PMN介导的内皮渗透性的增加……更多。使用抗CD18 MAB或抗粘附剂Leumedin抑制PMN粘附对内皮细胞的抑制作用也阻止了内皮渗透性的PMN介导的增加。这些发现表明，粘合剂事件对于介导PMN依赖性血管内皮通透性的增加至关重要。我们还研究了PMN对内皮屏障功能的迁移的影响。通过IL-8浓度梯度引起的内皮单层的PMN迁移并没有增加内皮的渗透性，但是当内皮单层以低浓度的TNFA预处理时，它确实会增加渗透性。 TNFA的这种作用被抗CD18 mAb抑制。据报道，据报道，反应性氧中间体（ROI）（例如过氧化氢）在急性肺损伤的病理生理学中起着重要作用，而不仅是终末效应，而且是信号传输途径的第二个使者。我们研究了ROI在粘合分子表达机理中的作用。 N-乙酰半胱氨酸（NAC）是一种抗氧化剂，改善了TNFA诱导的细胞间粘合分子-1（ICAM-1）在培养的人支气管上皮细胞（BEAS-2B）上的表达。 NAC还减弱了气管内LPS诱导的PMN疗程和大鼠肺中的ICAM-1表达。这些发现表明，肺中的粘附分子表达是由ROI.NF-kb激活的产生介导的，可能在该途径中涉及。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起着至关重要的作用治疗剂。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。”