Department of Internal Medicine, Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Wake Forest Critical Illness, Injury, and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
J Gerontol A Biol Sci Med Sci. 2021 Apr 30;76(5):770-777. doi: 10.1093/gerona/glaa248.
Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18-20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.
年龄增长是导致呼吸衰竭和急性呼吸窘迫综合征（ARDS）预后不良的一个危险因素。在这项研究中，我们试图确定在成年（6 个月）和老年（18-20 个月）雄性 C57BL/6 小鼠经气管内脂多糖（IT-LPS）急性肺损伤（ALI）后，肺部炎症、肌肉损伤和代谢方面与年龄相关的差异。我们还研究了肌肉脂肪酸氧化（FAO）的年龄相关变化以及药物 etomoxir 对全身 FAO 抑制的影响。老年小鼠的肺损伤过程具有明显特征，表现为肺泡中性粒细胞持续增多，对治疗性运动无反应。为了评估 ALI 的代谢后果，老年和成年小鼠在 IT-LPS 前后进行了全身代谢表型分析。老年小鼠表现出长时间的厌食和呼吸交换率降低，这表明它们对 FAO 的依赖性增加。Etomoxir 增加了老年而非成年 ALI 小鼠的死亡率，这证实了 FAO 在急性严重应激中的生存意义，并表明成年小鼠对 FAO 抑制具有更高的抵抗力。老年 ALI 小鼠的骨骼肌中关键脂肪酸代谢酶的转录物 CPT-1b、LCAD、MCAD、FATP1 和 UCP3 增加。此外，老年小鼠在基线和肺损伤后 CPT-1b 的蛋白水平增加。令人惊讶的是，与成年小鼠相比，老年小鼠分离的骨骼肌线粒体中的 CPT-1b 活性降低。老年 ALI 小鼠的独特表型与 ARDS 的不利年龄相关结局具有相似的特征。这种模型可能有助于检查和增强与危重病老年人群独特相关的免疫和代谢异常。
