Fredenburgh Laura E, Kraft Bryan D, Hess Dean R, Harris R Scott, Wolf Monroe A, Suliman Hagir B, Roggli Victor L, Davies John D, Winkler Tilo, Stenzler Alex, Baron Rebecca M, Thompson B Taylor, Choi Augustine M, Welty-Wolf Karen E, Piantadosi Claude A
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina;
Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L834-46. doi: 10.1152/ajplung.00240.2015. Epub 2015 Aug 28.
Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically relevant baboon model of Streptococcus pneumoniae pneumonia to 1) test a novel, ventilator-compatible CO delivery system; 2) establish a safe and effective CO dosing regimen; and 3) investigate the local and systemic effects of CO therapy on inflammation and acute lung injury (ALI). Animals were inoculated with S. pneumoniae (10(8)-10(9) CFU) (n = 14) or saline vehicle (n = 5); in a subset with pneumonia (n = 5), we administered low-dose, inhaled CO gas (100-300 ppm × 60-90 min) at 0, 6, 24, and/or 48 h postinoculation and serially measured blood carboxyhemoglobin (COHb) levels. We found that CO inhalation at 200 ppm for 60 min is well tolerated and achieves a COHb of 6-8% with ambient CO levels ≤ 1 ppm. The COHb level measured at 20 min predicted the 60-min COHb level by the Coburn-Forster-Kane equation with high accuracy. Animals given inhaled CO + antibiotics displayed significantly less ALI at 8 days postinoculation compared with antibiotics alone. Inhaled CO was associated with activation of mitochondrial biogenesis in the lung and with augmentation of renal antioxidative programs. These data support the feasibility of safely delivering inhaled CO gas during mechanical ventilation and provide preliminary evidence that CO may accelerate the resolution of ALI in a clinically relevant nonhuman primate pneumonia model.
如果能够开发出一种安全、基于证据的给药策略以及一种与呼吸机兼容的一氧化碳（CO）输送系统，吸入一氧化碳气体对急性呼吸窘迫综合征患者具有治疗潜力。在本研究中，我们使用了肺炎链球菌肺炎的临床相关狒狒模型，以1）测试一种新型的、与呼吸机兼容的CO输送系统；2）建立一种安全有效的CO给药方案；3）研究CO治疗对炎症和急性肺损伤（ALI）的局部和全身影响。动物接种肺炎链球菌（10⁸ - 10⁹ CFU）（n = 14）或生理盐水载体（n = 5）；在一部分患有肺炎的动物（n = 5）中，我们在接种后0、6、24和/或48小时给予低剂量吸入CO气体（100 - 300 ppm×60 - 90分钟），并连续测量血液碳氧血红蛋白（COHb）水平。我们发现，吸入200 ppm的CO 60分钟耐受性良好，在环境CO水平≤1 ppm时可使COHb达到6 - 8%。通过Coburn - Forster - Kane方程在20分钟时测量的COHb水平能够高精度预测60分钟时的COHb水平。与单独使用抗生素相比，吸入CO + 抗生素的动物在接种后8天显示出明显更少的ALI。吸入CO与肺中线粒体生物发生的激活以及肾脏抗氧化程序的增强有关。这些数据支持了在机械通气期间安全输送吸入CO气体的可行性，并提供了初步证据表明CO可能在临床相关的非人灵长类肺炎模型中加速ALI的消退。
