Controlling Bacterial Biofilms in Cystic Fibrosis Airways

控制囊性纤维化气道中的细菌生物膜

基本信息

批准号：
7851093
负责人：
GERARD C WONG
金额：
$ 26.36万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

项目摘要

In this proposal, we describe a new pathway signaling PMN influx and damage to the airways that may play a role as an initiator or cofactor for chronic obstructive pulmonary disease (COPD). Specifically, chemical or enzymatic breakdown of collagen releases a tripeptide, PGP, and/or a related PGP-containing sequence that is chemotactic for PMN in vitro. We demonstrate that introduction of PGP into the airways causes a robust influx of PMN, but not monocytes. Remarkably, the PMN chemotactic activity of PGP may be due to a marked structural relatedness to a receptor binding domain of CXC chemokines such as IL-8 which contain this collagen sequence or a close analog. Prolonged airway exposure to this peptide causes alveolar enlargement and right ventricular hypertrophy and thus recapitulates aspects of COPD. Furthermore, using electrospray ionization-liquid chromatography-mass spectrometry (ESI-LC-MS/MS), PGP is found in the airways of animals exposed to aerosolized LPS and markedly contributes to PMN influx. We have converted PGP from a CXC receptor (R) agonist to a partial agonist and finally an antagonist by systematically exchanging L with D isomers of P on the N and/or C termini. (D-P)G(D-P) antagonizes PGP as well as IL-8 chemotactic activity in vitro. We have found that PGP is present in bronchoalveolar lavage fluids (BALF) and/or sputum from virtually all COPD patients but not controls or asthmatics. Furthermore, sputum from COPD patients but not control individuals contains all the enzymatic machinery necessary for the ex vivo generation of PGP from purified collagen. Collectively, these findings lead us to hypothesize that PGP represents a novel biomarker for COPD that may contribute to disease. As a corollary, we theorize that PGP represents an attractive therapeutic target in COPD. These hypotheses will be tested via a multidisciplinary, multifaceted approach to develop (D-P)G(D-P) as a new therapeutic that will simultaneously inhibit both the IL- 8 and PGP pathways of neutrophilic inflammation and, consequently, may be useful in the management of COPD. In addition, we will evaluate PGP as a novel biomarker for COPD as well as a prognosticator of potential utility of (D-P)G(D-P) as a therapeutic agent.

在此提案中，我们描述了一种新的途径信号传达PMN涌入和对气道的损害，可能在慢性阻塞性肺部疾病（COPD）中起发挥作用或辅助因子的作用。具体而言，胶原蛋白的化学或酶促分解释放三肽，PGP和/或相关的含PGP的序列，该序列是PMN体外趋化性的。我们证明，将PGP引入气道会导致PMN的强劲涌入，但并非单核细胞。值得注意的是，PGP的PMN趋化活性可能是由于与CXC趋化因子（例如IL-8）的受体结合结构域的明显结构相关性，例如IL-8，其中包含该胶原蛋白序列或近距离类似物。长时间的气道暴露于该肽会导致肺泡扩大和右心室肥大，从而概括COPD的各个方面。此外，使用电喷雾电离 - 液相色谱 - 质量光谱法（ESI-LC-MS/MS），在暴露于雾化的LP的动物的气道中发现了PGP，并显着有助于PMN涌入。我们已经将PGP从CXC受体（R）激动剂转化为部分激动剂，最后是通过系统地与N和/或C末端的P异构体交换L的l异构体。（D-P）G（D-P）在体外拮抗PGP以及IL-8趋化活性。我们发现，几乎所有COPD患者的支气管肺泡灌洗液（BALF）（BALF）和/或痰中存在PGP，但没有对照或哮喘患者。此外，来自COPD患者但不能对照个体的痰液中包含了从纯化胶原蛋白的实体生成PGP所需的所有酶促机制。总的来说，这些发现使我们假设PGP代表了COPD的新型生物标志物，可能会导致疾病。作为推论，我们认为PGP代表COPD中有吸引力的治疗靶标。这些假设将通过多学科的多方面方法进行检验（D-P）G（D-P）作为一种新的治疗方法，该方法将同时抑制中性粒细胞炎症的IL-8和PGP途径，因此可能在管理中可能有用。 COPD。此外，我们将评估PGP作为COPD的新型生物标志物，以及（D-P）G（D-P）作为治疗剂的潜在效用的预后。