Examining Carbon Monoxide to Treat Inflammatory Conditions using Experimental Colitis Models

摘要 一氧化碳（CO）是与一氧化氮（NO）同等重要的内源性信号分子， 1998年诺贝尔奖得主。它是由血红素加氧酶降解血红素产生的。广泛 文献报道已经令人信服地证明了CO作为抗炎剂的治疗效果 在结肠炎、败血症、肝损伤和器官移植的模型中。虽然关于药物的功效已知很多， CO，现在的挑战是开发可药用的可输送形式的CO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一直是主要的递送形式。然而，在这方面， 这不是理想的方式，因为难以安全给药和控制剂量，缺乏 便携性，以及对每个患者的呼吸功能的依赖性，以提供精确的量。 也已经有许多基于金属的CO释放分子（CO-RM）和光敏的CO释放分子。 有机CO-RM。然而，金属毒性和光可及性问题施加了限制。在一个令人兴奋 在开发过程中，我们已经开发了几类具有可调释放速率的有机CO-前药。我们 建议探索使用这种前药治疗炎症和组织损伤的潜力， 小鼠实验性结肠炎（EC）作为模型。其他人和我们已经证明了CO的独特能力， 减轻炎症，促进组织修复，增强宿主对病原性细菌感染的防御。 因此，CO具有成为结肠炎有效治疗的巨大潜力，而不会增加结肠炎的风险。 与广泛免疫抑制相关的感染。随着药物发现和开发的高成本 这远远超出了NIH应用程序中可用的资金，我们计划首先检查一组定义明确的 问题.具有可调释放速率的前药的可用性首次提供了检查 剂量、功效、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， 气体传送器在这个MPI应用程序中，我们联合收割机结合了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CO前药 EC模型中的炎症。我们的中心假设是CO-前药通过以下方式在EC中起治疗作用： 调节肠道微环境。我们将通过以下两个具体目标进行测试：1）合成， 优化和评估CO前药;和2.）评价EC中的CO前药。我们的初步结果清楚地表明 显示了这种CO-前药在治疗鼠EC、脓毒症和肝损伤中的功效。完成后 项目，我们希望有：1。开发了一系列CO前药，2.）证明了使用 这些前药治疗EC模型中的炎症;和（3）定义了剂量、释放之间的关系 动力学、药代动力学和功效，具有明确的治疗窗。基于CO的临床潜力 治疗作为抗炎剂是深刻的，并可能影响其他领域， 移植中风和心脏病

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.