Mesenchymal Stromal Cell Conditioning by Carbon Monoxide

一氧化碳调理间充质基质细胞

基本信息

批准号：
8225579
负责人：
Mark A PERRELLA
金额：
$ 49.48万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225579
关键词：
Acute Lung Injury Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Automobile Driving Bacteria Biological Biological Assay Bone Marrow Carbon Monoxide Cell Communication Cell Therapy Cell surface Cells Cessation of life Coculture Techniques Complex Conditioned Culture Media Death Rate Diagnosis Disease Early treatment Effector Cell Event Exposure to Failure Fibroblasts Functional disorder Gases Goals Harvest Hematopoietic Heme Home environment Homeostasis Homing Hour Human Hypotension Hypoxia Immune Immune Cell Activation Immune response Immune system Infection Inflammation Inflammatory Inflammatory Response Injury Invaded Knockout Mice Laboratories Lead Ligation Lung Lymphocyte Mediator of activation protein Medical Mesenchymal Molecular Mus Organ Organ Survival Organism Outcome Oxygenases Patients Phagocytes Phagocytosis Process Property Pulmonary Circulation Puncture procedure Refractory Resolution Respiratory Failure Role Sepsis Septic Shock Severities Site Staging Stromal Cells Therapeutic Time Transgenic Mice Wound Healing antimicrobial base conditioning heme oxygenase-1 improved improved functioning in vivo innovation insight lung injury macrophage microbial microorganism monocyte neutrophil novel novel strategies novel therapeutics overexpression paracrine pathogen pre-clinical prevent response

项目摘要

PROJECT SUMMARY (See instmctions): Sepsis is a disease process representing the systemic response to severe infection. The infectious insult activates immune cells of the host, including neutrophils, monocytes/macrophages, and lymphocytes. Early activation of immune cells triggers a pro-inflammatory response that contributes to eradication of the invading microorganism(s). If the pathogens are not eradicated, sepsis may progress to severe sepsis (sepsis plus organ dysfunction, such as lung injury and respiratory failure) and septic shock (severe sepsis plus refractory hypotension and circulatory failure), which frequently leads to death. Once the invading microorganism(s) are eradicated, then resolution of the immune response is critical, as continued systemic inflammation will lead to organ injury. Unfortunately, this early pro-inflammatory response may also be followed by a later state of immunoparalysis, due in part to apoptosis of immune effector cells. The cascade of biologic events that occur during sepsis is complex, and therapeutic strategies need to be tailored depending upon the stage of sepsis at the time of diagnosis. Multipotent mesenchymal stromal cells (MSCs) are considered to be a promising platform for cell-based therapy. MSCs are known to have immunomodulatory properties, and recently it has been suggested that MSCs are beneficial during the early proinflammatory stage of cecal ligation and puncture in mice. We hypothesize that MSCs, when administered to mice after the onset of polymicrobial or single organism sepsis, will adapt to the specific stage of sepsis and lead to an improved outcome. Prior studies in our laboratory demonstrated that heme oxygenase (H0)-1-derived carbon monoxide (CO), a known anti-inflammatory molecule, also has anti-microbial properties during sepsis. Thus, we also hypothesize that conditioning MSCs with CO ex vivo will improve their function In vivo, and increase the beneficial effects of MSCs after the onset of sepsis in mice. Gaining insight into the mechanisms responsible for this enhanced response of MSCs conditioned with CO will allow us to further understand MSCs as a cell-based therapy, and to develop novel therapeutic strategies for this devastating disease process. MSCs ¿ CO conditioning will also be studied in mice with a "humanized" immune system. Finally we will advance the understanding of the human immune response to sepsis by assessing phagocytic function of neutrophils and monocytes harvested from patients with sepsis or sepsis plus acute lung injury, compared with cells from control patients. We will determine whether the administration of MSCs ¿ CO ex vivo can improve phagocyte function. These functional assays will be correlated with patient outcome.

项目摘要（请参阅Instmctions）：败血症是代表对严重感染的全身反应的疾病过程。感染性损伤激活宿主的免疫细胞，包括中性粒细胞，单核细胞/巨噬细胞和淋巴细胞。免疫细胞的早期激活触发了促炎反应，这有助于入侵微生物的辐射。如果未放射病原体，败血症可能会发展为严重的败血症（败血症加器官功能障碍，例如肺损伤和呼吸衰竭）和败血性休克（严重的败血症加上难治性低血压和电路失败），这经常导致死亡。一旦入侵的微生物放射放射性，则免疫增强响应的分辨率至关重要，因为持续的全身感染将导致器官损伤。不幸的是，这种早期促炎反应也可能是后来的免疫分析状态，部分原因是免疫效应细胞的凋亡。败血症期间发生的一系列生物事件是复杂的，并且需要根据诊断时败血症的阶段来量身定制治疗策略。多态性间充质基质细胞（MSC）被认为是基于细胞治疗的有前途的平台。已知MSC具有免疫调节特性，最近有人提出，在小鼠的盲肠结扎和穿刺的早期促炎阶段，MSC是有益的。我们假设MSC在多肌醇或单一生物体败血症发作后将MSC施用时，将适应败血症的特定阶段，并导致改善的结果。在我们的实验室中的先前研究表明，已知的抗炎分子（H0）-1衍生的一氧化碳（CO）（CO）在败血症期间也具有抗微生物特性。因此，我们还假设通过CO EX VIVO的调理MSC将改善其在体内的功能，并增加败血症开始后MSC的有益作用。洞悉负责以CO为条件的MSC这一增强反应的机制将使我们能够进一步将MSC理解为基于细胞的治疗，并为这种毁灭性的疾病过程制定新的治疗策略。 MSCS�CO调节也将在具有“人性化”免疫系统的小鼠中研究。最后，与对照患者的细胞相比，我们将通过评估从脓毒症或败血症或脓毒症加急性肺损伤的患者收获的中性粒细胞和单核细胞的嗜中性粒细胞和单核细胞的静脉功能来提高对败血症的理解。我们将确定MSCS的施用是否可以改善吞噬细胞功能。这些功能测定将与患者结局相关。