Pulmonary Biomarkers of Inflammation in Chronic Tetraplegia

描述（由申请人提供）： 四肢瘫痪者表现出肺功能障碍，这归因于呼吸肌麻痹，导致通气不足和无法清除分泌物，使这一人群更容易反复肺部感染。除了观察到的限制性肺功能障碍外，患有高颈病变的个体通常表现出与哮喘患者相似的阻塞性呼吸生理学，并且被认为是由于对气道的无对抗的副交感神经支配以及可能的对肺的交感神经支配的丧失。基础气道炎症是哮喘个体的主要病理生理机制。类似地，气道炎症可能在四肢瘫痪个体中观察到的阻塞性生理学中起作用。我们来自题为“一氧化氮对四肢瘫痪患者肺阻力和血压的影响”（RCDA #B4162 C-Radulovic）的项目的初步数据表明，慢性稳定性四肢瘫痪患者的呼出一氧化氮（FeNO）水平增加，与轻度哮喘受试者的水平相当，表明存在潜在的气道炎症。在呼出气冷凝物（EBC）中发现的气道炎症的更特异性生物标志物的测量将能够更好地定义慢性四肢瘫患者呼吸道中潜在气道炎症的存在，并可能解决导致气道炎症的因素。因此，反过来，可以导致新的治疗策略的开发，例如在该人群中使用吸入性类固醇，并可能降低呼吸系统并发症的发生率，减少再住院的数量并改善受影响个体的生活质量。本研究的目的是确定慢性稳定性四肢瘫患者呼出的炎症生物标志物的存在/不存在及其与FeNO和整体肺功能的关系。了解慢性颈脊髓损伤患者肺功能障碍的潜在机制，可以确定治疗方案，如使用吸入性类固醇。这种方法有望最终改善受影响个体的生活质量，降低因呼吸系统并发症而再次住院的比率，并减轻SCI患者和医疗保健系统的社会经济负担。 公共卫生相关性： 拟定工作与VA患者护理使命的相关性。 退伍军人事务部的使命是为所有患者提供最佳的临床护理。与身体健全的退伍军人相比，SCI患者需要与神经功能缺损程度直接相关的专门护理。重要的是要认识和解决瘫痪的继发性并发症，以提高SCI患者的寿命和生活质量。这项研究可能有助于开发新的成本效益的治疗方法，用于治疗和预防呼吸系统并发症。显著的系统范围的成本节约可能会导致我们的方法，以更高的脊髓病变的退伍军人的改进。 增加我们对慢性颈脊髓损伤患者阻塞性呼吸功能障碍的潜在机制的理解对于指导未来的临床干预至关重要。潜在炎症的发现提示使用特定的抗炎剂进行治疗。如果找不到炎症的标志物，反过来又会提示神经功能受损，并增加替代治疗的可能性，如吸入L-NAME。减少慢性四肢瘫痪患者的潜在气道炎症有望降低与呼吸系统并发症相关的死亡率和发病率，呼吸系统并发症是SCI急性期死亡的主要原因，也是慢性颈脊髓损伤患者再次住院的第三大原因。除了减少呼吸系统并发症外，整体呼吸功能的改善预计将提高生活质量，对就业能力，个人活动和运动训练具有潜在影响。肺部护理的进步有望转化为受影响个体更有成效、更积极和更独立的生活方式。降低慢性颈脊髓损伤患者的住院率将显著降低提供护理的经济负担。

DESCRIPTION (provided by applicant): Persons with tetraplegia exhibit pulmonary dysfunction attributed to paralysis of respiratory muscles leading to inadequate ventilation and inability to clear secretions, predisposing this population to be more susceptible to repeated pulmonary infections. In addition to restrictive pulmonary dysfunction observed, individuals with high cervical lesion often exhibit obstructive respiratory physiology similar to that seen in asthmatics and believed to be due to unopposed parasympathetic innervation to the airways and, possibly, the loss of sympathetic innervation to the lungs. Underlying airway inflammation is the major pathophysiological mechanism in individuals with asthma. Similarly, airway inflammation may play a role in the obstructive physiology observed in individuals with tetraplegia. Our preliminary data from project entitled "The Effect of Nitric Oxide on Pulmonary Resistances and Blood Pressure in Persons with Tetraplegia" (RCDA #B4162C-Radulovic) has demonstrated that individuals with chronic stable tetraplegia have increased levels of fractional exhaled nitric oxide (FeNO) comparable to levels in mild asthmatic subjects, suggesting the presence of underlying airway inflammation. Measurement of more specific biomarkers of airway inflammation that are found in exhaled breath condensates (EBC) will enable better definition of the presence of and, potentially, address contributing factors leading to underlying airway inflammation in the respiratory tract of individuals with chronic tetraplegia. Thus, in turn, can result in development of new therapeutic strategies, such as use of inhaled steroids in this population, and potentially decrease the rate of respiratory complications, decreasing the number of re-hospitalizations and improving the quality of life of affected individuals. The purpose of this study is to determine the presence/absence of exhaled biomarkers of inflammation in individuals with chronic stable tetraplegia and their relationship with FeNO and overall pulmonary function. Understanding the underlying mechanisms involved in pulmonary dysfunction observed in persons with chronic cervical SCI may identify treatment options, such as use of inhaled steroids. This approach would be expected to ultimately improve quality of life in affected individuals, decreasing the rate of re-hospitalizations due to respiratory complications and the socioeconomic burden placed on these with SCI and the health care system. PUBLIC HEALTH RELEVANCE: Relevance of the Proposed Work to the VA Patient Care Mission. The Mission of the Department of Veterans Affairs is to provide optimal clinical care for all patients. Compared with able-bodied veterans, persons with SCI require specialized care directly related to the degree of neurologic impairment. It is important to recognize and address the secondary complications of paralysis to improve the longevity and quality of life of persons with SCI. This study may facilitate the development of new cost effective therapeutic approaches for the treatment and prevention of respiratory complications. Significant system- wide cost-savings may result from improvements in our approach to veterans with higher cord lesions. Increasing our understanding of the underlying mechanisms of obstructive respiratory dysfunction observed in individuals with chronic cervical SCI is of utmost importance for guiding future clinical interventions. The finding of underlying inflammation would suggest therapeutic use of specific anti-inflammatory agents. Failing to find markers of inflammation would, in turn, suggest neurological impairment and raise the possibility of alternative treatments, such as inhaled L-NAME. Reduction of underlying airway inflammation in persons with chronic tetraplegia would be expected to reduce the mortality and morbidity associated with respiratory complications, which are the leading cause of mortality during the acute phase of SCI and third leading cause of re-hospitalization in persons with chronic cervical SCI. Apart from decreasing respiratory complications, improvement of overall respiratory function would be expected to increase the quality of life, with potential implications on employability, personal activities, and exercise training. Advances in pulmonary care would be expected to translate into more productive, active and independent lifestyles for affected individuals. Decreasing the rates of hospitalization for individuals with chronic cervical SCI would significantly decrease the financial burden of providing care.