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Basic Study on Lung Injuries and Neutrophils-Isolation and Purification of Alveolus-Derived Neutrophil Inhibitory Factor and Its Effects on The Development of Lung Injuries-

肺损伤与中性粒细胞的基础研究-肺泡源性中性粒细胞抑制因子的分离纯化及其对肺损伤发生发展的影响-

基本信息

批准号：
08670650
负责人：
SUWABE Akira
金额：
$ 1.09万
依托单位：
YAMAGATA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670650/
关键词：
LUNG INJURY NEUTROPHILS SUPEROXIDES SURFACTANT

项目摘要

In the development of lung injury, the infiltrating neutrophils and their injury-causative agents, such as protease or active oxygen radicals are mainly involved. Most of the therapies have not been effective for those disease states and the prognosis of these patients are still poor.We have focused on the neutrophil inhibitory factors found in the pulmonary alveolus. In a series of these studies, we reported that rat lung surfactant and rat alveolar type II cells directory inhibited human neutrophil superoxide production. We also found another neutrophil inhibitory factors in the soluble fraction of the bronchoalveolar lavage fluids in rats. These inhibitory activities were destroyed by treating the samples at 100ﾟC for 10min, suggesting that inhibition was derived from the protein components. The inhibitory factors were also shown to be different from those previously described, such as superoxide disumutase (SOD) and were expected to be new therapeutic agents for the patients with l … More ung injuries.In the researches in 1996, we have shown that the inhibitory effect was independent of that by surfactant specific proteins, such as SP-A or SP-D.In the next year, we focused on one of the inhibitory cytokines, transforming growth factor-beta (TGF-beta) as the candidate of neutrophil inhibitory factors. We tried the experiments (1) showing whether human TGF-beta can inhibit human neutrophil functions, (2) measuring the TGF-beta concentration in the lung lavage fluids, and (3) neutralizing the inhibitory activities by anti-TGF-beta antibodies. The results, however, were not satisfactory by the reasons of the species difference between human and rats, the high nonspecific adsorbent activity of this cytokine. Although we determined the approximate molecular weight of these inhibitory activities around 200-300 kDa, we were unable to purify these inhibitory proteins since inhibitory activities were lost during the purification procedures. The goal of the present study has not been achieved at this point, but we further need to purify these inhibitory molecules and to establish the specific monoclonal antibody recognizing these molecules. Less

在肺损伤的发展过程中，主要涉及浸润性中性粒细胞及其损伤病原体，例如蛋白酶或活性氧自由基。大多数治疗方法对这些疾病状态无效，这些患者的预后仍然很差。我们重点关注肺泡中发现的中性粒细胞抑制因子。在一系列这些研究中，我们报道了大鼠肺表面活性物质和大鼠肺泡 II 型细胞目录抑制人中性粒细胞超氧化物的产生。我们还在大鼠支气管肺泡灌洗液的可溶部分中发现了另一种中性粒细胞抑制因子。在 100°C 下处理样品 10 分钟后，这些抑制活性被破坏，表明抑制作用来自于蛋白质成分。抑制因子也被证明与之前描述的不同，例如超氧化物歧化酶（SOD），有望成为肺部损伤患者的新治疗剂。在1996年的研究中，我们已经表明，抑制作用与表面活性剂特异性蛋白（例如SP-A或SP-D）的抑制作用无关。在接下来的一年里，我们将重点放在其中一种抑制性细胞因子上，转化生长 β因子（TGF-β）作为中性粒细胞抑制因子的候选者。我们尝试了以下实验：（1）显示人TGF-β是否可以抑制人中性粒细胞功能，（2）测量肺灌洗液中的TGF-β浓度，以及（3）中和抗TGF-β抗体的抑制活性。然而，由于人和大鼠之间的物种差异以及该细胞因子的高非特异性吸附活性等原因，结果并不令人满意。尽管我们确定这些抑制活性的大致分子量约为 200-300 kDa，但我们无法纯化这些抑制蛋白，因为在纯化过程中抑制活性丢失。目前本研究的目的尚未达到，但我们还需要纯化这些抑制分子并建立识别这些分子的特异性单克隆抗体。较少的