Is impaired fracture healing in smokers related to CO exposure?

描述（由申请人提供）：骨折修复背后的细胞生物学是非常显著的。尽管存在高能量损伤、骨折部位大面积移位、严重的骨粉碎，甚至节段性骨丢失，但大多数骨折以简单的方式愈合，患者通常恢复大部分（如果不是全部）损伤前功能。然而，尽管骨骼具有强大的愈合反应，但仍有5%至8%的患者骨折不能愈合，进展为骨不连。从临床角度来看，这组不愈合的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。对于严重损伤，如开放性胫骨骨折，在某些系列中，再手术率超过60%，即使骨折愈合后，患者报告的结果仍然很差。从基础科学和临床角度来看，吸烟对骨折愈合有不利影响，这一点已得到广泛认可。虽然这种愈合不良和吸烟之间的联系是明确的，但烟草烟雾毒性的根本原因尚不清楚。最近的研究强调了缺氧信号在缺氧诱导因子（HIF）通路中对软骨细胞发育和骨折修复至关重要的作用，从而提出了吸烟者骨折愈合受损与一氧化碳暴露和HIF信号紊乱有关的假设。我们进一步假设，这种效果可以通过使用脯氨酰羟化酶抑制剂来改善，恢复细胞对缺氧的反应，并允许HIF产物的积累。作为一名学术实践中的骨科创伤外科医生，我花了几年的时间来发展必要的经验和技能，以追求我的兴趣，研究骨折修复的细胞生理学。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。通过这一提议，我寻求进一步发展基础科学培训和技能，我将需要作为一名独立研究者进行高质量和临床相关的研究。此外，确定烟草烟雾中的致病毒素具有明确的临床意义，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群体中出现的并发症。

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.