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首页> 外文学位 >Perfluorochemical augmented intratracheal delivery of antioxidant enzymes and genes to attenuate oxidative stress-induced lung and respiratory muscle alterations.
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Perfluorochemical augmented intratracheal delivery of antioxidant enzymes and genes to attenuate oxidative stress-induced lung and respiratory muscle alterations.

机译：全氟化物增强了气管内抗氧化酶和基因的传递，以减轻氧化应激诱导的肺和呼吸肌的改变。

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摘要

Supraphysiologic concentrations of oxygen are used in the management of critically ill patients across the lifespan. However, hyperoxia (HO) results in alveolar-capillary membrane destruction, pulmonary edema, pleural effusions, infiltration and activation of inflammatory cells, altered pulmonary mechanics and gas exchange prompting increased loading of the respiratory muscle. These abnormalities of pulmonary structure and function increase the work of breathing necessitating increased respiratory muscle force production to maintain alveolar ventilation. When the load placed on the respiratory muscle pump exceeds its capacity, respiratory failure develops and is ultimately fatal unless therapeutic interventions are able to reduce the ventilatory load.;The use of perfluorochemical (PFC) liquids as a respiratory medium has been effective in the treatment of respiratory distress syndrome and acute lung injury (ALI) requiring mechanical ventilation. Mechanistically, by eliminating the air-liquid interface, PFC liquids reduce surface tension enabling lung volume recruitment at low inspiratory pressures and have high respiratory gas solubility which supports gas exchange. Additionally, through mechanical as well as cytoprotective mechanisms, intrapulmonary PFC liquids reduce inflammatory cell activation and recruitment. Cell culture, animal and human studies have suggested that acute and chronic lung injury secondary to prolonged HO may be ameliorated by administration of antioxidant enzymes (AOE), with superoxide dismutases (SOD) having significant protective effects. Because the lung is exposed to the highest O2 concentrations, a logical strategy to reduce HO-induced damage is to specifically target antioxidant enzymes to the lungs. However, intratracheal delivery of AOE by vehicles like normal saline may transiently impair lung function and be poorly distributed. PFC fluids have previously been shown to be effective respiratory media for pulmonary administration of various drugs.;The premise of the proposed studies are to characterize hyperoxic lung injury in a spontaneously breathing animal model and to develop therapeutic strategies to reduce oxidatative stress and supplement endogenous AOE. With respect to the diaphragm, we reason that HO-induced lung damage and oxidative stress will increase contractile demand of the diaphragm. If AOE activity could be increased in the lungs and respiratory muscles with AOE proteins or the genes encoding these enzymes, then cell damage, inflammatory changes, damage to the lung and respiratory "pump" might be ameliorated or prevented. The results show that PFC and SOD can attenuate the HO-induced decline in lung mechanics and gas exchange, ameliorate the inflammatory and oxidative stress profiles, and promote lung and muscle structural integrity resulting in a survival benefit. These findings support the novel application of PFC liquids in a spontaneously breathing model and support the concept that PFC preconditioning and AOE supplementation play a protective role by reducing mortality and morbidity in hyperoxic lung injury.
机译：超生理学浓度的氧气用于整个生命周期内危重病人的管理。但是，高氧（HO）会导致肺泡毛细血管膜破坏，肺水肿，胸腔积液，炎性细胞的浸润和活化，改变的肺力学和气体交换，从而导致呼吸肌负荷增加。肺部结构和功能的这些异常增加了呼吸的工作，因此需要增加呼吸肌力的产生来维持肺泡通气。当施加在呼吸肌泵上的负荷超过其能力时，除非治疗干预能够降低通气负荷，否则呼吸衰竭会发展并最终致命。;使用全氟化物（PFC）液体作为呼吸介质已在治疗中有效需要机械通气的呼吸窘迫综合征和急性肺损伤（ALI）。从机械上讲，通过消除气液界面，PFC液体可降低表面张力，从而可在低吸气压力下募集肺体积，并具有高呼吸气体溶解度，从而支持气体交换。此外，通过机械和细胞保护机制，肺内PFC液体可减少炎症细胞的活化和募集。细胞培养，动物和人类研究表明，长期服用HO引起的急性和慢性肺损伤可通过施用抗氧化酶（AOE）来缓解，其中超氧化物歧化酶（SOD）具有明显的保护作用。由于肺部暴露于最高的O2浓度，因此减少HO诱导的损伤的合理策略是将抗氧化酶专门靶向肺部。然而，媒介物（如生理盐水）在气管内递送AOE可能会暂时损害肺功能并且分布不佳。先前已证明PFC流体是用于多种药物肺部给药的有效呼吸介质。;拟议的研究的前提是在自发呼吸的动物模型中表征高氧性肺损伤并制定治疗策略以减轻氧化应激并补充内源性AOE 。对于隔膜，我们认为HO诱导的肺损伤和氧化应激会增加隔膜的收缩需求。如果可以使用AOE蛋白或编码这些酶的基因在肺和呼吸肌中提高AOE活性，则可以改善或预防细胞损伤，炎症变化，肺和呼吸“泵”损伤。结果表明，PFC和SOD可以减轻HO诱导的肺力学和气体交换下降，改善炎症和氧化应激状况，促进肺和肌肉结构完整性，从而带来生存优势。这些发现支持PFC液体在自发呼吸模型中的新应用，并支持PFC预处理和AOE补充通过降低高氧性肺损伤的死亡率和发病率起到保护作用的概念。

著录项

  • 作者

    Malone, Daniel Joseph.;

  • 作者单位

    Temple University.;

  • 授予单位 Temple University.;
  • 学科 Health Sciences Medicine and Surgery.;Biology Physiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 284 p.
  • 总页数 284
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 R501;R601;
  • 关键词

  • 入库时间 2022-08-17 11:38:30

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