Kwon Oh Sung, Smuder Ashley J, Wiggs Michael P, Hall Stephanie E, Sollanek Kurt J, Morton Aaron B, Talbert Erin E, Toklu Hale Z, Tumer Nihal, Powers Scott K
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida;
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida; and Geriatric Research, Education, and Clinical Center, North Florida/South Georgia Veterans Health System, Gainesville, Florida.
J Appl Physiol (1985). 2015 Nov 15;119(10):1033-41. doi: 10.1152/japplphysiol.00237.2015. Epub 2015 Sep 10.
Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness, which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remain unknown. However, recent evidence reveals that increased plasma levels of angiotensin II (ANG II) result in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of ANG II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma ANG II levels, and the ANG II type 1 receptor antagonist (losartan) was provided to prevent the activation of ANG II type 1 receptors. Enalapril prevented the increase in plasma ANG II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. These findings indicate that circulating ANG II is not essential for the development of ventilator-induced diaphragm weakness but that activation of ANG II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration-approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans.
机械通气是呼吸衰竭患者的一种挽救生命的干预措施。不幸的是，长时间的呼吸机支持会导致膈肌萎缩和收缩功能障碍，进而导致膈肌无力，这预计会导致患者撤机困难。虽然已经确定呼吸机诱导的氧化应激是呼吸机诱导的膈肌无力发展所必需的，但触发氧化剂产生的信号通路仍然未知。然而，最近的证据表明，血浆中血管紧张素II（ANG II）水平升高会导致肢体骨骼肌氧化应激和萎缩。我们使用一种成熟的机械通气动物模型，测试了以下假设：循环中ANG II水平升高是呼吸机诱导的膈肌氧化应激和膈肌无力所必需的。通过给予血管紧张素转换酶抑制剂（依那普利）来预防呼吸机诱导的血浆ANG II水平升高以确定因果关系，并给予ANG II 1型受体拮抗剂（氯沙坦）来预防ANG II 1型受体的激活。依那普利可预防血浆ANG II水平升高，但不能预防呼吸机诱导的膈肌氧化应激或膈肌无力。相比之下，氯沙坦可减轻呼吸机诱导的氧化应激和膈肌无力。这些发现表明，循环中的ANG II对于呼吸机诱导的膈肌无力的发展并非必不可少，但ANG II 1型受体的激活似乎是呼吸机诱导的膈肌无力的必要条件。重要的是，这些实验提供了首个证据，即美国食品药品监督管理局批准的药物氯沙坦可能对预防人类呼吸机诱导的膈肌无力具有临床益处。
