Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury.
Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury.
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DOI：
10.1172/jci.insight.98546
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发表时间：
2018-01
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影响因子：
8
通讯作者：
C. Shaver;N. Wickersham;J. McNeil;H. Nagata;A. Miller;S. Landstreet;Jamie L. Kuck;J. Diamond;D. Lederer;S. Kawut;S. Palmer;K. Wille;A. Weinacker;V. Lama;M. Crespo;J. Orens;P. Shah;C. Hage;E. Cantu;M. Porteous;G. Dhillon;J. McDyer;J. Bastarache;Jason D. Christie;L. Ware
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文献类型：
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作者：
C. Shaver;N. Wickersham;J. McNeil;H. Nagata;A. Miller;S. Landstreet;Jamie L. Kuck;J. Diamond;D. Lederer;S. Kawut;S. Palmer;K. Wille;A. Weinacker;V. Lama;M. Crespo;J. Orens;P. Shah;C. Hage;E. Cantu;M. Porteous;G. Dhillon;J. McDyer;J. Bastarache;Jason D. Christie;L. Ware
原发性移植物功能障碍（PGD）是指肺移植术后72小时内的急性肺损伤。我们假设无细胞血红蛋白（CFH）通过增加肺微血管通透性来促进PGD，并在患者、离体人肺和培养的人肺微血管内皮细胞中进行了测试。在一项巢式病例对照研究中，40例72小时严重PGD患者和80例无PGD的匹配对照中，术前CFH升高与PGD风险增加独立相关（优势比[OR] 2.75, 95%CI, 1.23-6.16, P = 0.014）。再灌注吸入氧分数(FiO2)≥0.40时，CFH对PGD的影响被放大（OR 3.41, P = 0.031）。暴露于血管内CFH （100 mg/dl）的离体灌注人肺通过肺重量测量血管通透性增加（CFH为14.4%，对照组为0.65%,P = 0.047）， Evans蓝色标记白蛋白染料（EBD）外渗到空气中（P = 0.027）。CFH （1 mg/dl）也增加了人肺微血管内皮细胞单层（hPMVECs）的细胞旁通透性。与常氧（FiO2 = 0.21）相比，高氧（FiO2 = 0.95）增加了人肺和hPMVEC的通透性。对乙酰氨基酚（15 μg/ml）可抑制cfh依赖性肺通透性（P = 0.046）和hPMVECs （P = 0.037）。综上所述，CFH可能通过对微血管通透性的氧化作用介导PGD，高氧增强了这一作用，对乙酰氨基酚消除了这一作用。
Primary graft dysfunction (PGD) is acute lung injury within 72 hours of lung transplantation. We hypothesized that cell-free hemoglobin (CFH) contributes to PGD by increasing lung microvascular permeability and tested this in patients, ex vivo human lungs, and cultured human lung microvascular endothelial cells. In a nested case control study of 40 patients with severe PGD at 72 hours and 80 matched controls without PGD, elevated preoperative CFH was independently associated with increased PGD risk (odds ratio [OR] 2.75, 95%CI, 1.23-6.16, P = 0.014). The effect of CFH on PGD was magnified by reperfusion fraction of inspired oxygen (FiO2) ≥ 0.40 (OR 3.41, P = 0.031). Isolated perfused human lungs exposed to intravascular CFH (100 mg/dl) developed increased vascular permeability as measured by lung weight (CFH 14.4% vs. control 0.65%, P = 0.047) and extravasation of Evans blue-labeled albumin dye (EBD) into the airspace (P = 0.027). CFH (1 mg/dl) also increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers (hPMVECs). Hyperoxia (FiO2 = 0.95) increased human lung and hPMVEC permeability compared with normoxia (FiO2 = 0.21). Treatment with acetaminophen (15 μg/ml), a specific hemoprotein reductant, prevented CFH-dependent permeability in human lungs (P = 0.046) and hPMVECs (P = 0.037). In summary, CFH may mediate PGD through oxidative effects on microvascular permeability, which are augmented by hyperoxia and abrogated by acetaminophen.