Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.
JCI Insight. 2018 Jan 25;3(2). doi: 10.1172/jci.insight.98546.
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.
原发性移植物功能障碍（PGD）是肺移植后 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导致 PGD，并在患者、离体人肺和培养的人肺微血管内皮细胞中对此进行了测试。在一项嵌套病例对照研究中，对 40 例 72 小时时发生严重 PGD 的患者和 80 例无 PGD 的匹配对照患者进行了研究，术前 CFH 升高与 PGD 风险增加独立相关（比值比[OR]2.75，95%CI，1.23-6.16，P=0.014）。CFH 对 PGD 的影响因再灌注时吸入氧分数（FiO2）≥0.40 而放大（OR3.41，P=0.031）。用血管内 CFH（100mg/dl）处理的离体灌注人肺会导致血管通透性增加，如肺重量（CFH 14.4% vs. 对照 0.65%，P=0.047）和伊文思蓝标记白蛋白染料（EBD）渗出到肺泡腔（P=0.027）。CFH（1mg/dl）还增加了人肺微血管内皮细胞单层的细胞旁通透性。与常氧（FiO2=0.21）相比，高氧（FiO2=0.95）增加了人肺和 hPMVEC 的通透性。用醋氨酚（15μg/ml）治疗，一种特异性血红素蛋白还原剂，可防止 CFH 依赖的人肺（P=0.046）和 hPMVEC 通透性（P=0.037）。总之，CFH 可能通过对微血管通透性的氧化作用介导 PGD，这种作用在高氧和醋氨酚的作用下被放大。
