Polverino Francesca, Laucho-Contreras Maria E, Petersen Hans, Bijol Vanesa, Sholl Lynette M, Choi Mary E, Divo Miguel, Pinto-Plata Victor, Chetta Alfredo, Tesfaigzi Yohannes, Celli Bartolomé R, Owen Caroline A
1 Pulmonary Division and.
2 Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
Am J Respir Crit Care Med. 2017 Jun 1;195(11):1464-1476. doi: 10.1164/rccm.201609-1765OC.
Patients with chronic obstructive pulmonary disease (COPD) frequently have albuminuria (indicative of renal endothelial cell injury) associated with hypoxemia.
To determine whether (1) cigarette smoke (CS)-induced pulmonary and renal endothelial cell injury explains the association between albuminuria and COPD, (2) CS-induced albuminuria is linked to increases in the oxidative stress-advanced glycation end products (AGEs) receptor for AGEs (RAGE) pathway, and (3) enalapril (which has antioxidant properties) limits the progression of pulmonary and renal injury by reducing activation of the AGEs-RAGE pathway in endothelial cells in both organs.
In 26 patients with COPD, 24 ever-smokers without COPD, 32 nonsmokers who underwent a renal biopsy or nephrectomy, and in CS-exposed mice, we assessed pathologic and ultrastructural renal lesions, and measured urinary albumin/creatinine ratios, tissue oxidative stress levels, and AGEs and RAGE levels in pulmonary and renal endothelial cells. The efficacy of enalapril on pulmonary and renal lesions was assessed in CS-exposed mice.
Patients with COPD and/or CS-exposed mice had chronic renal injury, increased urinary albumin/creatinine ratios, and increased tissue oxidative stress and AGEs-RAGE levels in pulmonary and renal endothelial cells. Treating mice with enalapril attenuated CS-induced increases in urinary albumin/creatinine ratios, tissue oxidative stress levels, endothelial cell AGEs and RAGE levels, pulmonary and renal cell apoptosis, and the progression of chronic renal and pulmonary lesions.
Patients with COPD and/or CS-exposed mice have pulmonary and renal endothelial cell injury linked to increased endothelial cell AGEs and RAGE levels. Albuminuria could identify patients with COPD in whom angiotensin-converting enzyme inhibitor therapy improves renal and lung function by reducing endothelial injury.
慢性阻塞性肺疾病（COPD）患者常出现与低氧血症相关的蛋白尿（提示肾内皮细胞损伤）。
确定（1）香烟烟雾（CS）诱导的肺和肾内皮细胞损伤是否可解释蛋白尿与COPD之间的关联；（2）CS诱导的蛋白尿是否与氧化应激-晚期糖基化终产物（AGEs）受体（RAGE）通路的激活增加有关；（3）依那普利（具有抗氧化特性）是否通过减少两个器官内皮细胞中AGEs-RAGE通路的激活来限制肺和肾损伤的进展。
在26例COPD患者、24例既往吸烟的非COPD患者、32例接受肾活检或肾切除术的非吸烟者以及暴露于CS的小鼠中，我们评估了肾脏的病理和超微结构病变，并测量了尿白蛋白/肌酐比值、组织氧化应激水平以及肺和肾内皮细胞中的AGEs和RAGE水平。在暴露于CS的小鼠中评估依那普利对肺和肾损伤的疗效。
COPD患者和/或暴露于CS的小鼠存在慢性肾损伤、尿白蛋白/肌酐比值升高，以及肺和肾内皮细胞中的组织氧化应激和AGEs-RAGE水平升高。用依那普利治疗小鼠可减轻CS诱导的尿白蛋白/肌酐比值升高、组织氧化应激水平、内皮细胞AGEs和RAGE水平升高、肺和肾细胞凋亡以及慢性肾和肺病变的进展。
COPD患者和/或暴露于CS的小鼠存在与内皮细胞AGEs和RAGE水平升高相关的肺和肾内皮细胞损伤。蛋白尿可识别出COPD患者，对于这些患者，血管紧张素转换酶抑制剂治疗可通过减少内皮损伤来改善肾和肺功能。
