Examining Carbon Monoxide to Treat Inflammatory Conditions using Experimental Colitis Models

摘要 一氧化碳(CO)是一种与一氧化氮(NO)同等重要的内源性信号分子。 1998年诺贝尔奖的主题。它是由血红素加氧酶降解产生的。广泛性 文献报道已经令人信服地证明了一氧化碳作为抗炎剂的治疗作用。 在结肠炎、败血症、肝损伤和器官移植模型中。虽然我们已经知道了很多关于 CO，现在的挑战是开发药学上可接受的CO递送形式作为研究工具 以及可能的治疗方法。在大多数临床前工作中，吸入CO一直是主要的给药形式。然而， 这不是理想的方式，因为在安全给药和控制剂量方面存在困难，缺乏 可携带性，以及依赖于每个患者的呼吸功能来提供准确的数量。 也有一些基于金属的CO释放分子(CO-RMS)和光敏分子 有机CO-RMS。然而，金属毒性和光线可获得性问题造成了限制。在一个激动人心的时刻 在开发过程中，我们已经开发了几类释放率可调的有机前体药。我们 建议探索使用此类前药治疗炎症和组织损伤的潜力。 以小鼠实验性结肠炎(EC)为模型。其他人和我们已经展示了CO的独特能力 减少炎症，促进组织修复，增强宿主抵御病原菌感染的防御能力。 因此，一氧化碳有巨大的潜力成为结肠炎的有效治疗方法，而不会增加患结肠炎的风险。 感染与广泛的免疫抑制有关。由于药物发现和开发的成本很高 这远远超出了NIH应用程序的可用资金，我们计划首先检查一组定义良好的 问题。具有可调节释放率的前药的可用性提供了第一次检查的机会 剂量、疗效、药代动力学和释放曲线之间的相互作用，这是一个独特的问题 气体传感器。在此MPI应用程序中，我们结合了Wang、Tan和Otterbein的广泛专业知识 实验室，并建议在令人信服的初步数据的基础上开发用于治疗的有机前体药 EC模型中的炎症反应。我们的中心假设是，Co-前体药物通过以下途径在EC中发挥治疗作用 调节肠道微环境。我们将以以下两个具体目标来测试这一点：1)合成， 优化和评估一氧化碳前体药物；以及2.)对EC中CO-前体药物进行评价。我们的初步结果很清楚 展示了这种CO前体药在治疗小鼠EC、败血症和肝损伤方面的有效性。在完成 项目，我们期望有：1.)开发了一系列一氧化碳前体药物，2。)论证了使用的可行性 这些前药用于治疗EC模型中的炎症；以及(3)定义了剂量、释放之间的关系 药动学、药动学和疗效与一个明确的治疗窗口。一氧化碳的临床应用潜力 作为消炎剂的治疗是深远的，可能会影响其他领域，如器官 移植、中风和心脏病发作。

Abstract Carbon monoxide (CO) is an endogenous signaling molecule with importance on par with nitric oxide (NO), the subject of the 1998 Nobel Prize. It is produced from heme degradation by heme oxygenases. Extensive literature reports have convincingly demonstrated the therapeutic effects of CO as an anti-inflammatory agent in models of colitis, sepsis, liver injury, and organ transplant. While much is known regarding the efficacy of CO, the challenge now is to develop pharmaceutically acceptable deliverable forms of CO as research tools and possible therapeutics. Inhaled CO has been the major form of delivery in most preclinical work. However, this is not the ideal modality because of difficulties in safe administration and in controlling doses, lack of portability, and the dependence on each individual patient’s respiratory function to deliver precise amounts. There have also been a number of metal-based CO-releasing molecules (CO-RMs) and photo-sensitive organic CO-RMs. However, metal toxicity and light accessibility issues impose limitations. In an exciting development, we have developed several classes of organic CO-prodrugs with tunable release rates. We propose to explore the potential of using such prodrugs to treat inflammation and tissue injury using experimental colitis (EC) in mice as a model. Others and we have demonstrated the unique ability of CO to reduce inflammation, promote tissue repair, and enhance host defense against pathogenic bacterial infection. Therefore, CO has enormous potential to be an effective treatment for colitis without the increased risk of infection associated with broad immunosuppression. With the high cost of drug discovery and development which is way beyond the funds available in an NIH application, we plan to initially examine a well-defined set of issues. The availability of prodrugs with tunable release rates offers the opportunity for the first time to examine the interplay among dosage, efficacy, pharmacokinetics, and release profiles, which is a unique problem with a gasotranmistter. In this MPI application, we combine the extensive expertise of the Wang, Tan, and Otterbein labs, and propose to build on compelling preliminary data to develop organic CO-prodrugs for treating inflammation in EC models. Our central hypothesis is that CO-prodrugs acts therapeutically in EC by modulating the intestinal microenvironment. We will test this with the following 2 specific aims: 1.) synthesize, optimize, and assess CO prodrugs; and 2.) evaluate the CO-prodrugs in EC. Our preliminary results clearly show efficacy of such CO-prodrugs in treating murine EC, sepsis, and liver injury. Upon completion of the project, we expect to have: 1.) developed a series of CO prodrugs, 2.) demonstrated the feasibility of using such prodrugs to treat inflammation in EC models; and (3) defined the relationship among dose, release kinetics, pharmacokinetics and efficacy with a clear therapeutic window. The clinical potential of CO-based therapeutics as anti-inflammatory agents is profound and could impact other areas such as organ transplantation, stroke, and heart attack.