Regulatory Tcells and the fibroproliferative response in Acute Lung Injury

调节性 T 细胞和急性肺损伤中的纤维增殖反应

基本信息

批准号：
8136644
负责人：
Brian Garibaldi
金额：
$ 5.12万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136644
关键词：
Accounting Acute Lung Injury Adoptive Transfer Adult Respiratory Distress Syndrome Affect Animal Model Bleomycin Bone Marrow Cell Count Cell Culture Techniques Cells Coculture Techniques Collagen Conditioned Culture Media Data Deposition Development Diffuse Disease Edema Environmental air flow Enzyme-Linked Immunosorbent Assay Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibronectins Fibrosis Fluorescence-Activated Cell Sorting Future Goals Histology Hour Human Hyaluronan IL2RA gene Immunoblotting Immunohistochemistry In Vitro Individual Infiltration Inflammation Inflammatory Injury Laminin Lead Liquid substance Lung Lung Compliance Lung diseases Lymphocyte Macrophage Activation Measures Membrane Metalloproteases Modeling Morbidity - disease rate Mus Myofibroblast Outcome Pathogenesis Patients Phase Phenotype Play Proteins Rag1 Mouse Recruitment Activity Regulatory T-Lymphocyte Research Resolution Role Sampling Smooth Muscle Actin Staining Method Staging Staining method Stains Stem cells Stimulus Techniques Tidal Volume Tissues United States arm epithelial to mesenchymal transition improved in vivo inhibitor/antagonist injured interest lung injury macrophage mortality mouse model novel novel therapeutics public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Acute lung Injury (ALI) and the more severe Acute Respiratory Distress Syndrome (ARDS) are diffuse lung diseases that cause tremendous morbidity and mortality in the United States each year. Despite decades of research into the pathogenesis and mechanisms underlying the development of ARDS, mortality remains high and the only treatment shown to be effective is low tidal volume ventilation in patients who require ventilatory support. A subset of patients with ARDS progress to a fibroproliferative stage marked pathologically by fibrosis and clinically by increasing dead space, decreasing lung compliance and worsening oxygenation. Recent interest has shifted from the factors that promote the development of ALI to determinants of the resolution of lung injury. Regulatory T cells (Tregs) have been found to be critical to the resolution of ALI in a mouse model of LPS-induced lung injury. They have also been shown to increase in number in the BAL fluid of patients with ARDS, suggesting that they likely play an important role in the normal human response to ALI. The role of Tregs in the fibroproliferative response to ALI has not been studied. The goal of this proposal is to determine the role of Tregs in the fibroproliferative response to ALI, with the hope of identifying novel mechanisms that may ultimately lead to future treatment options in patients with ALI. In order to achieve this goal this proposal will utilize both in vivo and in vitro techniques to examine the role of Tregs in fibroproliferation after LPS-induced ALI. For the in vivo arm, C57BL/6 wildtype (WT) mice and Rag-1-/- lymphocyte deficient mice will be exposed to intratracheal (i.t.) LPS and the resulting fibroproliferative response will be rigorously phenotyped. Adoptive transfer of Tregs into Rag-1-/- mice will be employed to examine the specific effects of Tregs on the fibroproliferative response. In the in vitro experiments, fibroblasts will be grown in cell culture under various stimulating conditions. Tregs and macrophages will be added in different co-culture combinations to examine the cellular mechanisms by which Tregs modify fibroblast function. These experiments will explore new observations on the role of Tregs in the fibroproliferative response to ALI with the ultimate goal of improving patient outcomes in this oftentimes fatal disease. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) is a common and oftentimes fatal pulmonary disease that may result in lung fibrosis. T- regulatory (Treg) cells have been shown to be important in the resolution of ALI but their role in the development of fibrosis after ALI is unknown. We propose to study the effect of Tregs on the fibroproliferative response to ALI with the hope of identifying novel mechanisms that may ultimately lead to new therapeutic options for this disease.

描述（由申请人提供）：急性肺损伤 (ALI) 和更严重的急性呼吸窘迫综合征 (ARDS) 是弥漫性肺部疾病，每年在美国造成巨大的发病率和死亡率。尽管对 ARDS 发病机制和机制进行了数十年的研究，但死亡率仍然很高，对于需要通气支持的患者，唯一有效的治疗方法是低潮气量通气。一部分 ARDS 患者进展至纤维增殖期，病理上表现为纤维化，临床上表现为死腔增加、肺顺应性降低和氧合恶化。最近的兴趣已从促进 ALI 发展的因素转向肺损伤消退的决定因素。研究发现，在 LPS 诱导的肺损伤小鼠模型中，调节性 T 细胞 (Treg) 对于缓解 ALI 至关重要。研究还表明，ARDS 患者的 BAL 液中它们的数量有所增加，这表明它们可能在人类对 ALI 的正常反应中发挥着重要作用。 Tregs 在 ALI 纤维增殖反应中的作用尚未研究。该提案的目标是确定 Tregs 在 ALI 纤维增殖反应中的作用，希望确定可能最终为 ALI 患者带来未来治疗选择的新机制。为了实现这一目标，本提案将利用体内和体外技术来检查 Treg 在 LPS 诱导的 ALI 后纤维增殖中的作用。对于体内组，C57BL/6 野生型 (WT) 小鼠和 Rag-1-/- 淋巴细胞缺陷型小鼠将暴露于气管内 (i.t.) LPS，并对由此产生的纤维增殖反应进行严格的表型分析。将 Tregs 过继转移到 Rag-1-/- 小鼠中将用于检查 Tregs 对纤维增殖反应的具体影响。在体外实验中，成纤维细胞将在各种刺激条件下在细胞培养物中生长。 Tregs 和巨噬细胞将添加到不同的共培养组合中，以检查 Tregs 改变成纤维细胞功能的细胞机制。这些实验将探索 Tregs 在 ALI 纤维增殖反应中的作用的新观察结果，最终目标是改善这种常常致命的疾病的患者预后。公共卫生相关性：急性肺损伤 (ALI) 是一种常见且常常致命的肺部疾病，可能导致肺纤维化。 T 调节 (Treg) 细胞已被证明在 ALI 的缓解中发挥重要作用，但它们在 ALI 后纤维化发展中的作用尚不清楚。我们建议研究 Tregs 对 ALI 纤维增殖反应的影响，希望找到新的机制，最终为这种疾病带来新的治疗选择。