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: 3129433
• 负责人: Ricardo U. Sorensen
• 金额: $ 11.27万
• 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/3129433
• 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.

慢性进行性肺部感染的细菌病原体，特别是 铜绿假单胞菌是引起该病的主要原因。 囊性纤维化患者的死亡率。在初步研究中， 我们发现，感染铜绿假单胞菌的患者痰中含量很高。 抑制淋巴细胞增殖反应。抑制活性 存在于痰中的细菌具有耐热性。在平行研究中，我们发现 高效耐热抑制因子(S)对小鼠淋巴细胞增殖的影响 铜绿假单胞菌培养上清。这些抑制因素一直是 经鉴定为吩嗪类色素。这些化合物具有较低的抑制活性 相对分子质量的色素不被抗P。铜绿假单胞菌 抗体。 我们的第一个具体目标是鉴定抗热抑制剂(S) CF痰中的淋巴细胞增殖。为此， 将使用高分辨率层析和其他分析方法。 CF痰中抑制物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类色素和抑制剂的作用。 在CF痰中存在对淋巴细胞激活和吞噬细胞的影响 中性粒细胞和肺泡巨噬细胞的功能 (上午)。这些方法包括表面表达活化标记。 T淋巴细胞，B淋巴细胞分泌免疫球蛋白，以及 吞噬作用、亚硝酸四氮唑还原和铜绿假单胞菌摄取 被PMN和AM杀死。这些研究的后续目标是 定义直接从CF痰或支气管中获得的细胞的变化 洗澡。第三个具体目标是确定CF淋巴细胞或 中性粒细胞对铜绿假单胞菌吩嗪的抑制作用更敏感 比正常淋巴细胞或中性粒细胞更多的色素。最后一个特定目标是 寻找可能拮抗P。 铜绿假单胞菌。将使用以下方法寻求抑制-中和效果 抗抑制物抗体共价连接到载体上，或通过 与类似但非抑制性化合物的竞争抑制。 CF痰中耐热抑制物的存在可能会 在慢性肺感染的发生和发展中起重要作用。 需要了解这种抑制肺阻力的机制。 以设计特定的治疗方法来克服它。

项目成果

Chromobacterium violaceum adenitis acquired in the northern United States as a complication of chronic granulomatous disease.

紫色杆菌腺炎是在美国北部获得的，是慢性肉芽肿病的并发症。

• DOI: 10.1097/00006454-198511000-00028
• 发表时间: 1985
• 期刊: Pediatric infectious disease
• 作者: Sorensen,RU;Jacobs,MR;Shurin,SB
• 通讯作者: Shurin,SB

Suppression of lymphocyte proliferation by Pseudomonas aeruginosa phenazine pigments.

铜绿假单胞菌吩嗪色素抑制淋巴细胞增殖。

• 发表时间: 1988
• 期刊: Israel journal of medical sciences
• 作者: Nutman,J;Chase,PA;Dearborn,DG;Berger,M;Sorensen,RU
• 通讯作者: Sorensen,RU

Biological effects of Pseudomonas aeruginosa phenazine pigments.

铜绿假单胞菌吩嗪色素的生物学效应。

• DOI: 10.1159/000414339
• 发表时间: 1987
• 期刊: Antibiotics and chemotherapy
• 作者: Sorensen,RU;Klinger,JD
• 通讯作者: Klinger,JD

In vitro effect of synthetic pyocyanine on neutrophil superoxide production.

合成绿脓素对中性粒细胞超氧化物产生的体外影响。

• DOI: 10.1128/iai.55.3.559-563.1987
• 发表时间: 1987
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Miller,KM;Dearborn,DG;Sorensen,RU
• 通讯作者: Sorensen,RU

Long-term immunological reconstitution by peripheral blood leucocytes in severe combined immune deficiency disease: implications for the role of mature lymphocytes in histocompatible bone marrow transplantation.

严重联合免疫缺陷病中外周血白细胞的长期免疫重建：对成熟淋巴细胞在组织相容性骨髓移植中作用的影响。

• 发表时间: 1986
• 期刊: Clinical and experimental immunology
• 影响因子: 4.6
• 作者: Polmar,SH;Schacter,BZ;Sorensen,RU
• 通讯作者: Sorensen,RU