Neutrophil Collagenase in Sepsis and Ventilator Induced Lung Injury

脓毒症和呼吸机引起的肺损伤中的中性粒细胞胶原酶

• 批准号: 8115060
• 负责人: A. Murat Kaynar
• 金额: $ 12.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115060
• 关键词: Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacteria; Biological; Biology; Blood; Bone Marrow Transplantation; Bronchoalveolar Lavage; Cells; Chemotaxis; Critical Care; Cytology; Data; Development; Disease model; Dose; Fostering; Gene Targeting; Goals; Hematopoietic; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injury; Laboratories; Lead; Ligation; Lipopolysaccharides; Lung; Lung diseases; Macrophage Inflammatory Proteins; Matrix Metalloproteinases; Measures; Mechanical ventilation; Mediating; Medicine; Mentors; Mentorship; Modeling; Morbidity - disease rate; Multiple Organ Failure; Mus; Neutrophil Collagenase; Organ; Outcome; Pathogenesis; Patients; Pattern; Peptide Hydrolases; Peritoneal; Peritoneal lavage; Peritoneum; Phagocytosis; Play; Predisposition; Principal Investigator; Process; Property; Proteomics; Puncture procedure; Research; Research Proposals; Resolution; Resources; Role; Sampling; Scientist; Secondary to; Sepsis; Sepsis Syndrome; Severities; Site; Societies; Source; Structure of parenchyma of lung; Supportive care; System; Systemic infection; Testing; Therapeutic; Tidal Volume; Time; Tissues; Training Programs; Universities; Ventilator-induced lung injury; Wild Type Mouse; Work; base; career; chemokine; clinically relevant; cytokine; design; effective therapy; high risk; improved; insight; killings; lung injury; migration; mortality; mouse model; neutrophil; novel; prevent; proteinase In; reconstitution; research study; response

DESCRIPTION (provided by applicant): Sepsis is a major cause of morbidity and mortality occurring in around 700,000 individuals per year in US. Acute lung injury (All) in patients with sepsis is common, and carries a high mortality (-40%). Adequate and timely neutrophil response to the site of infection could limit sepsis in patients, yet uncontrolled accumulation of these cells could also lead to end-organ damage, one of the major reasons for multiple organ failure, including ALL Chemotaxis of neutrophils to the site of infection or inflammation are essential to this process. In this proposal we are going to study the central role of matrix metalloproteinase (MMP)-8 in neutrophil chemotaxis in models of sepsis, ventilator-induced lung injury (VILI) and the combination of sepsis-induced lung injury with subsequent VILI. Our preliminary data suggests that MMP-8 limits the neutrophil chemotaxis into sites of inflammation/infection. This property of MMP-8 is deleterious in our sepsis model of cecal- ligation and puncture, where the MMP-8 deficient mice had a significant survival advantage. On the other hand, the lack of MMP-8 led to inappropriate accumulation of neutrophils in the lung tissues in mice on mechanical ventilation and led to significant VILI. The research proposal will serve as a training program for the applicant with a focus on MMP-8 biology in the setting of clinically relevant questions, a perfect fit for a candidate on the path of becoming a clinician-scientist. This application takes advantage of the diversity of resources available within the Department of Medicine and Critical Care Medicine at the University of Pittsburgh to provide the principal investigator with a unique training program designed to foster a successful research career under the mentorship of Dr. Steven D. Shapiro. The experimental approach is unique in that it utilizes a murine model of (i) extra-pulmonary sepsis, (ii) ventilator-induced lung injury, and (iii) the modulating effects of concomitant mechanical ventilation in the setting of sepsis-related ALI to study the role of MMP-8. Specific aims include: 1) mechanism of MMP-8 dependent bacterial clearance in a sepsis model, 2) role of MMP-8 in VILI, and 3) MMP-8 dependent cytokine inactivation, including proteomic approaches. Results are expected to yield fundamental insights into the MMP-8 biology in clinically relevant disease models and possibly provide the basis for development of novel anti-inflammatory therapeutic strategies for sepsis and ALI. Acute lung injury in the setting of systemic infection and inflammation such as sepsis carries a high risk for mortality. In this proposal, we will study a key molecule, namely matrix metalloproteinase (MMP)-8 in mouse models of sepsis, acute lung injury and the possible injury inflicted by the use of mechanical ventilation.

描述（由申请人提供）：败血症是美国每年约70万人发病和死亡率的主要原因。败血症患者的急性肺损伤（全部）很常见，并且死亡率很高（-40％）。对感染部位的适当和及时的中性粒细胞反应可能会限制患者的败血症，但是这些细胞的不受控制的积累也可能导致末端器官损伤，这是多器官衰竭的主要原因之一，包括中性粒细胞的所有趋化性造成感染部位或炎症的位点，对此过程至关重要。在该提案中，我们将研究脓毒症，呼吸机诱导的肺损伤（VILI）模型中嗜中性粒细胞趋化性基质金属蛋白酶（MMP）-8的核心作用，以及败血症诱导的肺损伤与随后的VILI的组合。我们的初步数据表明，MMP-8将中性粒细胞趋化性限制为炎症/感染部位。 MMP-8的这种特性在我们的败血症模型和穿刺模型中是有害的，其中MMP-8缺陷小鼠具有显着的生存优势。另一方面，缺乏MMP-8导致小鼠在机械通气中的肺组织中嗜中性粒细胞的积累不当，并导致了显着的VILI。该研究建议将作为申请人的培训计划，重点关注MMP-8生物学，以设置临床相关问题，非常适合成为临床医生科学家的候选人。该应用程序利用了匹兹堡大学医学和重症监护医学系中可用的资源多样性，为首席研究员提供了一项独特的培训计划，旨在在史蒂文·D·夏皮罗（Steven D. Shapiro）博士的指导下培养成功的研究职业。实验方法是独一无二的，因为它利用了（i）肺外败血症，（ii）呼吸机诱导的肺损伤的鼠模型，以及（iii）伴随机械通气的调节作用在败血症相关的ALI的环境中研究MMP-8的作用。具体目的包括：1）败血症模型中MMP-8依赖细菌清除的机制，2）MMP-8在VILI中的作用，以及3）MMP-8依赖性细胞因子失活，包括蛋白质组学方法。预计结果有望在临床相关疾病模型中对MMP-8生物学产生基本见解，并可能为败血症和ALI的新型抗炎治疗策略提供基础。 在全身感染和炎症（例如脓毒症）的情况下，急性肺损伤具有高死亡风险。在此提案中，我们将研究一个关键分子，即脓毒症的小鼠模型，急性肺损伤以及使用机械通气造成的损伤。