Is impaired fracture healing in smokers related to CO exposure?

描述(申请人提供)：骨折修复背后的细胞生物学是相当了不起的。尽管有高能量损伤、骨折部位的大范围移位、骨的剧烈粉碎，甚至节段性骨丢失，但大多数骨折以一种简单的方式愈合，患者经常恢复大部分(如果不是全部)损伤前的功能。然而，尽管骨骼有很强的愈合反应，大约5%到8%的患者不能愈合他们的骨折，进展到骨不连。从临床的角度来看，这组骨不连患者同样遭受严重的残疾，经常需要多次手术，发病率增加，甚至失去肢体。对于严重的损伤，如开放性胫骨骨折，某些系列的再手术率超过60%，即使骨折愈合后，患者报告的结果仍然普遍较差。从基础科学和临床角度来看，吸烟对骨折愈合都有不利影响，这一点得到了广泛的认可。虽然愈合不良和吸烟之间的这种联系是明确的，但烟草烟雾毒性的潜在原因尚不清楚。最近的工作强调了通过低氧诱导因子(HIF)途径的低氧信号在软骨细胞发育和骨折修复中的关键作用，导致了吸烟者骨折愈合受损与一氧化碳暴露和HIF信号紊乱有关的假说。我们进一步假设，这一效应可以通过使用Pro羟化酶抑制剂来改善，恢复细胞对低氧的反应，并允许HIF产物的积累。作为一名在学术实践中实习的整形外科创伤外科医生，我花了几年的时间发展必要的经验和技能，以追求我的兴趣，研究骨折修复背后的细胞生理学。我在这方面得到了指导，并使用已建立的动物模型进行了体内骨折研究。通过这项建议，我寻求进一步发展基础科学培训和技能集，作为一名独立研究员，我将需要进行高质量和与临床相关的研究。此外，识别烟草烟雾中的致病毒素具有明确的临床意义，有可能支持使用经皮尼古丁和/或药物治疗来克服这一高危患者组中出现的并发症。

DESCRIPTION (provided by applicant): The cellular biology underlying fracture repair is quite remarkable. Despite high energy injuries, wide displacement at the fracture site, dramatic comminution of the bone, and even segmental bone loss, most fracture heal in an uncomplicated fashion and patients frequently recover most, if not all, of their pre-injury functio. Yet despite the skeleton's robust healing response, some 5 to 8% of patients do not heal their fractures, progressing on to nonunion. From a clinical standpoint, this group of patients with nonunion suffer equally dramatic disability, frequently requiring multiple surgeries, with increased morbidity and even loss of limb. For severe injuries, such as open tibia fractures, reoperation rates exceed 60% in some series, and patient reported outcomes even after the fracture is healed remain uniformly poor. It is widely recognized from both a basic science and a clinical perspective that smoking tobacco adversely affects fracture healing. While this association between poor healing and smoking is clear, the underlying cause of the toxicity in tobacco smoke is not known. Recent work has highlighted the role of hypoxic signaling through the Hypoxia Inducible Factor (HIF) pathway as critical for chondrocyte development and fracture repair, leading to the hypothesis that the impaired fracture healing in smokers is related to carbon monoxide exposure and disordered HIF signaling. We further hypothesize that this effect can be ameliorated by the use of prolyl hydroxylase inhibitors, restoring the cellular response to hypoxia and allowing for the accumulation of HIF products. As a practicing orthopedic trauma surgeon in an academic practice, I have spent several years developing the experience and skills necessary to pursue my interests investigating the cellular physiology underlying fracture repair. I have been mentored in this pursuit, and have conducted in vivo fracture studies using an established animal model. Through this proposal, I seek to further develop the basic science training and skill set I will need to pursue high quality and clinically relevant investigations asan independent investigator. In addition, identifying causative toxins in tobacco smoke has clear clinical implications, potentially supporting the use of transdermal nicotine and/or pharmacologic treatment to overcome the complications seen in this high risk group of patients.