CYSTIC FIBROSIS LUNG IMMUNITY AND PSEUDOMONAS INFECTION

囊性纤维化肺免疫和假单胞菌感染

• 批准号: 3129432
• 负责人: Ricardo U. Sorensen
• 金额: $ 10.53万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1986-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3129432
• 关键词: Pseudomonas aeruginosa; alveolar macrophages; bacterial disease; bacterial pigment; chronic disease /disorder; cystic fibrosis; diagnostic respiratory lavage; high performance liquid chromatography; human tissue; leukocyte activation /transformation; lymphocyte; mass spectrometry; medical complication; neutrophil; phagocytosis; phenazines; radiotracer; respiratory infections; sputum; tissue /cell culture; virulence

Chronic progressive lung infection with bacterial pathogens, particularly Pseudomonas aeruginosa, is responsible for most of the morbidity and mortality in patients with cystic fibrosis (CF). In preliminary studies, we have found that the sputum of P. aeruginosa infected patients is highly inhibitory for lymphocyte proliferative responses. The inhibitory activity present in the sputum is heat resistant. In parallel studies we have found potent, heat resistant inhibitory factor(s) for lymphocyte proliferation in P. aeruginosa culture supernatants. These inhibitory factors have been identified as phenazine pigments. The inhibitory activity of these low molecular weight pigments is not neutralized by anti-P. aeruginosa antibodies. Our first specific aim is to identify the heat resistant inhibitor(s) of lymphocyte proliferation which are present in CF sputum. To this effect, high resolution chromatography and other analytical methods will be used. The presence of inhibitors in CF sputum will be correlated with bacterial infection and functional inhibitory activity. The second specific aim is to establish the effect of P. aeruginosa phenazine pigments and inhibitors present in CF sputa on lymphocyte activation, and on phagocytic capabilities of polymorphonuclear cells (PMN's) and alveolar macrophages (AM). These methods include surface expression of activation markers on T-lymphocytes, secretion of immunoglobulins by B-lymphocytes, and phagocytosis, nitrobluetetrazolium reduction and P. aeruginosa uptake and killing by PMN's and AMs. The subsequent goal of these studies is to define alterations in cells obtained directly from CF sputum or bronchial lavage. The third specific aim is to establish whether CF lymphocytes or PMN's are more susceptible to inhibition by P. aeruginosa phenazine pigments than are normal lymphocytes or PMN's. A last specific aim is to search for possible antagonists for lymphocytes inhibitors produced by P. aeruginosa. An inhibition-neutralizing effect will be sought using antibodies to an inhibitor covalently attached to a carrier, or through competitive inhibition with similar but non-inhibitory compounds. The presence of heat resistant inhibitors in CF sputum is likely to contribute to the chronicity and progression of CF pulmonary infection. This mechanism of inhibition of pulmonary resistance needs to be understood in order to design specific therapeutic approaches to overcome it.

细菌病原体引起的慢性进行性肺部感染，特别是 铜绿假单胞菌是造成大部分发病率和 囊性纤维化（CF）患者的死亡率。 在初步研究中， 我们发现，铜绿假单胞菌感染患者的痰液中含有大量的铜绿假单胞菌。 抑制淋巴细胞增殖反应。 抑制活性 痰中存在的物质具有耐热性。 在平行研究中我们发现 淋巴细胞增殖的有效、耐热抑制因子 铜绿假单胞菌培养物上清液。 这些抑制因素 鉴定为吩嗪颜料。 这些低抑制活性 分子量颜料不会被抗 P 中和。铜绿假单胞菌 抗体。 我们的第一个具体目标是确定耐热抑制剂 CF痰中存在淋巴细胞增殖。 为此， 将使用高分辨率色谱法和其他分析方法。 CF 痰液中抑制剂的存在将与细菌相关 感染和功能抑制活性。 第二个具体目标是 确定铜绿假单胞菌吩嗪色素和抑制剂的作用 存在于 CF 痰液中，影响淋巴细胞活化和吞噬细胞 多形核细胞 (PMN) 和肺泡巨噬细胞的功能 （是）。 这些方法包括激活标记的表面表达 T 淋巴细胞、B 淋巴细胞分泌免疫球蛋白，以及 吞噬作用、硝基蓝四唑还原和铜绿假单胞菌摄取和 被 PMN 和 AM 杀死。 这些研究的后续目标是 定义直接从 CF 痰液或支气管中获得的细胞的变化 灌洗。 第三个具体目标是确定 CF 淋巴细胞或 PMN 更容易受到铜绿假单胞菌吩嗪的抑制 色素比正常淋巴细胞或 PMN 的色素要多。 最后一个具体目标是 寻找 P. 产生的淋巴细胞抑制剂的可能拮抗剂。 铜绿假单胞菌。 将使用以下方法寻求抑制中和作用 共价连接到载体上的抑制剂的抗体，或通过 与类似但非抑制性化合物的竞争性抑制。 CF 痰中存在耐热抑制剂可能 导致 CF 肺部感染的慢性化和进展。 需要了解这种抑制肺阻力的机制 以便设计具体的治疗方法来克服它。