Role of hemeoxygenase-1 in experimental acute pancreatitis

hemeoxygenase-1 在实验性急性胰腺炎中的作用

基本信息

批准号：
8334575
负责人：
Aida Habtezion
金额：
$ 34.52万
依托单位：
STANFORD UNIVERSITY
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：
2011-09-20 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334575
关键词：
Accounting Acinar Cell Admission activity Adoptive Transfer Alcohol abuse Alcohols Alternative Therapies Anti-Inflammatory Agents Anti-inflammatory Behavior Biliary Biliverdine Biological Assay Blocking Antibodies Bone Marrow Calculi Carbon Monoxide Cell Death Cell Therapy Cells Characteristics Cholelithiasis Clinical Coculture Techniques Colitis Coupled Cytoprotection Data Disease Drug Formulations Endothelial Cells Evaluation Excision Experimental Models FDA approved Figs - dietary Goals Heme Hemin Hemoglobin Hospitals Immune In Vitro Inflammatory Intercellular Adhesion Molecules Intercellular adhesion molecule 1 Iron Lead Lymphocyte Measures Mediating Modeling Molecular Mus Pancreas Pancreatic Diseases Pancreatic Injury Pathogenesis Patients Peptide Hydrolases Precipitating Factors Prosthesis Recruitment Activity Relative (related person)Risk Factors Role Signal Transduction Site Small Interfering RNA Source Specific qualifier value Spleen Supportive care Testing Therapeutic United States Vascular Cell Adhesion Molecule-1 Water acute pancreatitis attenuation base burden of illness cell injury cytokine diabetic gastroparesis effective therapy heme oxygenase-1 high risk in vivo macrophage monocyte mortality polarized cell protective effect receptor trafficking

项目摘要

DESCRIPTION (provided by applicant): Acute pancreatitis (AP) remains a challenging clinical problem, particularly in patients with severe disease. Despite its disease burden, therapy remains supportive at best coupled with removal of precipitating factors that may include alcohol or biliary obstructing calculi. Previously we showed a protective efect of hemin (hemoglobin prosthetic moiety that upregulates hemeoxygenase-1, HO-1) in experimental AP via recruitment of HO-1+ F4/80+ cells to the pancreas. More recently, we showed that Panhematin (PH, an FDA-approved water soluble formulation of hemin) induces rapid HO-1+ cell recruitment and treats ongoing experimental AP. Given these results, we propose to test the hypothesis that HO-1 downstream effectors and hemin primed cell- based transfers offer alternative therapeutic means for treating AP. Furthermore, we propose to define the source, characteristics, and mechanisms for monocyte recruitment and acinar cell protection. The specific aims of our proposal are: Aim 1: Determine the therapeutic role of HO-1 downstream effectors and evaluate the role for cell-based therapy in experimental acute pancreatitis. We propose to define the therapeutic role of HO-1 downstream effectors and PH-primed cells in treating AP. Aim 2: Characterize HO-1+ monocytes/macrophages recruitment to the inflamed pancreas following hemin treatment. We propose to characterize the monocytes recruited to the pancreas following PH treatment and ases their polarization into macrophages using phenotypic and functional assays. Aim 3: Define the mechanism of HO-1+ monocyte protection against pancreatic acinar cell injury. We propose here to determine mechanisms via which HO-1+ monocytes interact and protect against acinar cell injury. Aim 4: Characterize molecular and cellular determinants via which HO-1+ monocytes are recruited to the inflamed pancreas. In this aim, we propose to define trafficking molecule expression and then assess their functional role using blocking antibodies and/or mice genetically deficient in specified trafficking receptors. Evaluation of PH/HO-1 downstream effectors and interaction of PH-primed monocytes with acinar cells should help define PH's mechanism of action and offer alternate means of treating AP. Relative to lymphocyte trafficking, monocyte recruitment to various inflammatory sites is not as well-defined, and even less so to the pancreas. Findings from this project could lead to a better understanding of disease pathogenesis and mechanisms for immune cell recruitment to the inflamed pancreas.

描述（由申请人提供）：急性胰腺炎（AP）仍然是一个具有挑战性的临床问题，特别是对于患有严重疾病的患者。尽管存在疾病负担，治疗最多仍然是支持性的，同时消除可能包括酒精或胆道阻塞性结石在内的诱发因素。此前，我们通过将 HO-1+ F4/80+ 细胞募集至胰腺，在实验性 AP 中展示了氯高铁血红素（上调血红素加氧酶-1，HO-1 的血红蛋白修复部分）的保护作用。最近，我们发现 Panhematin（PH，一种 FDA 批准的氯化血红素水溶性制剂）可诱导 HO-1+ 细胞快速募集并治疗正在进行的实验性 AP。鉴于这些结果，我们建议检验以下假设：HO-1 下游效应器和氯化血红素引发的细胞转移为治疗 AP 提供了替代治疗方法。此外，我们建议定义单核细胞募集和腺泡细胞保护的来源、特征和机制。我们提案的具体目标是：目标 1：确定 HO-1 下游效应器的治疗作用并评估基于细胞的治疗在实验性急性胰腺炎中的作用。我们建议定义 HO-1 下游效应器和 PH 引发细胞在治疗 AP 中的治疗作用。目标 2：表征氯高铁血红素治疗后向发炎胰腺募集的 HO-1+ 单核细胞/巨噬细胞的特征。我们建议对 PH 处理后招募到胰腺的单核细胞进行表征，并使用表型和功能测定将其极化为巨噬细胞。目标 3：明确 HO-1+ 单核细胞保护胰腺腺泡细胞损伤的机制。我们在此建议确定 HO-1+ 单核细胞相互作用并防止腺泡细胞损伤的机制。目标 4：表征 HO-1+ 单核细胞被募集至发炎胰腺的分子和细胞决定因素。为此，我们建议定义贩运分子表达，然后使用阻断抗体和/或特定贩运受体遗传缺陷的小鼠评估其功能作用。评估 PH/HO-1 下游效应器以及 PH 引发的单核细胞与腺泡细胞的相互作用应有助于确定 PH 的作用机制并提供治疗 AP 的替代方法。相对于淋巴细胞运输，单核细胞向各种炎症部位的募集并不明确，对于胰腺来说更是如此。该项目的研究结果可能有助于更好地了解疾病发病机制和免疫细胞招募到发炎胰腺的机制。