Host Defense Mechanisms in Chronic Lung Disease

慢性肺病的宿主防御机制

• 批准号: 7917413
• 负责人: JO RAE WRIGHT
• 金额: $ 271.98万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-19 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917413
• 关键词: Host; Defense; Mechanisms; Chronic; Lung

The overall goal of this SCCOR proposal is to elucidate the roles of innate and adaptive immunity in the pathogenesis of chronic lung disease. The SCCOR proposal consists of four interrelated research projects that are focused on two chronic lung diseases: asthma and bronchiolitis obliterans syndrome (BOS) with a common underlying theme of epithelial injury, inflammation, repair and fibroproliferation. The central hypothesis to be tested is that chronic lung disease occurs as a consequence of destructive or maladaptive host responses to common environmental insults that challenge the lung. The fundamental roles of innate and adaptive host responses are to recognize invading antigens, pathogens or altered self components with the purpose of eradicating the offending agents and restoring tissue integrity. While resolution can occur when the host response is normal, an exogenous insult cannot be contained when a critical host factor is inactivated, dysregulated, or becomes dysfunctional. Such maladaptive host responses lead to chronic lung disease. The project specific hypotheses within this SCCOR proposal are: Project 1: Surfactant proteins SP-A and SP-D, which are produced by both alveolar and airway cells, interact with cells of both the adaptive and innate immune systems to coordinately maximize defense against inhaled allergens and that cause and exacerbate asthma, while minimizing an over exuberant immune response that could result in inflammation, tissue damage and chronic lung disease. Project 2: Interleukin 13 (IL-13) modulates airway fibroblast function in human asthma via increased expression of platelet-derived growth factor (PDGF), an adaptive host response, and subsequent airway remodeling via fibroblast proliferation, collagen expression and decreased elastin expression. Project 3: Activation of innate immunity through toll like receptors (TLRs) in the transplanted lung promotes the adaptive alloimmune response leading to acute rejection and BOS. Project 4: Innate immune mechanisms regulate chronic inflammation and tissue remodeling and specifically, host hyaluronan and TLR interactions are critical components of the injury and repair response in non-infectious lung injury, BOS and chronic asthma. These studies will contribute to our understanding of normal and altered host responses on lung structure and function and will provide a basis for investigation and development of new therapies for the treatment of chronic lung diseases.

该 SCCOR 提案的总体目标是阐明先天免疫和适应性免疫在慢性肺病发病机制中的作用。 SCCOR 提案由四个相互关联的研究项目组成，重点关注两种慢性肺部疾病：哮喘和闭塞性细支气管炎综合征 (BOS)，其共同的基本主题是上皮损伤、炎症、修复和纤维增殖。待检验的中心假设是，慢性肺病的发生是由于宿主对常见环境损害对肺部的破坏性或适应不良反应造成的。先天性和适应性宿主反应的基本作用是识别入侵的抗原、病原体或改变的自身成分，目的是根除有害物质并恢复组织完整性。虽然当宿主反应正常时可以解决问题，但当关键宿主因子失活、失调或功能失调时，外源性损伤就无法得到遏制。这种适应不良的宿主反应会导致慢性肺部疾病。 此 SCCOR 提案中的项目具体假设是： 项目 1：由肺泡和气道细胞产生的表面活性蛋白 SP-A 和 SP-D，与适应性免疫系统和先天免疫系统的细胞相互作用，协调最大程度地防御吸入性过敏原，避免引起和加剧哮喘，同时最大限度地减少吸入性过敏原的发生。过度旺盛的免疫反应可能导致炎症、组织损伤和慢性肺部疾病。 项目 2：白细胞介素 13 (IL-13) 通过增加血小板衍生生长因子 (PDGF) 的表达、适应性宿主反应以及随后通过成纤维细胞增殖、胶原蛋白表达和减少弹性蛋白表达进行气道重塑来调节人类哮喘中的气道成纤维细胞功能。 项目 3：通过移植肺中的 Toll 样受体 (TLR) 激活先天免疫，促进适应性同种免疫反应，导致急性排斥反应和 BOS。 项目 4：先天免疫机制调节慢性炎症和组织重塑，特别是宿主透明质酸和 TLR 相互作用是非感染性肺损伤、BOS 和慢性哮喘损伤和修复反应的关键组成部分。 这些研究将有助于我们了解正常和改变的宿主对肺结构和功能的反应，并将为研究和开发治疗慢性肺病的新疗法提供基础。

项目成果

Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients.

双侧肺移植受者闭塞性细支气管炎综合征后的生存率。

• 发表时间: 2010-09-15
• 影响因子: 24.7
• 作者: Finlen Copeland, C Ashley;Snyder, Laurie D;Zaas, David W;Turbyfill, W Jackson;Davis, W Austin;Palmer, Scott M
• 通讯作者: Palmer, Scott M

Acute cellular rejection and humoral sensitization in lung transplant recipients.

肺移植受者的急性细胞排斥和体液致敏。

• 发表时间: 2010-04
• 影响因子: 3.2
• 作者: Martinu, Tereza;Howell, David N;Palmer, Scott M
• 通讯作者: Palmer, Scott M

Surfactant protein-A inhibits mycoplasma-induced dendritic cell maturation through regulation of HMGB-1 cytokine activity.

表面活性蛋白 A 通过调节 HMGB-1 细胞因子活性来抑制支原体诱导的树突状细胞成熟。

• 发表时间: 2010-10-01
• 作者: Ledford, Julie G;Lo, Bernice;Kislan, Michele M;Thomas, Joseph M;Evans, Katherine;Cain, Derek W;Kraft, Monica;Williams, Kristi L;Wright, Jo Rae
• 通讯作者: Wright, Jo Rae

Polyfunctional cytomegalovirus-specific immunity in lung transplant recipients receiving valganciclovir prophylaxis.

接受缬更昔洛韦预防的肺移植受者的多功能巨细胞病毒特异性免疫。

• 发表时间: 2011-03
• 作者: Snyder, L D;Medinas, R;Chan, C;Sparks, S;Davis, W A;Palmer, S M;Weinhold, K J
• 通讯作者: Weinhold, K J

Allogeneic splenocyte transfer and lipopolysaccharide inhalations induce differential T cell expansion and lung injury: a novel model of pulmonary graft-versus-host disease.

同种异体脾细胞转移和脂多糖吸入诱导差异性 T 细胞扩增和肺损伤：肺移植物抗宿主病的一种新模型。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Martinu, Tereza;Kinnier, Christine V;Sun, Jesse;Kelly, Francine L;Nelson, Margaret E;Garantziotis, Stavros;Foster, W Michael;Palmer, Scott M
• 通讯作者: Palmer, Scott M