Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy.
Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy.
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DOI：
10.1097/shk.0000000000000188
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Doerschug KC
中科院分区：
文献类型：
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作者：
Gores KM;Delsing AS;Kraus SJ;Powers L;Vaena DA;Milhem MM;Monick M;Doerschug KC
脓毒症引起的肺损伤的病理生理学和治疗选择仍然难以捉摸。高剂量白细胞介素-2疗法（HDIL-2）是治疗晚期恶性肿瘤的重要方案，但受到全身炎症和肺水肿（与脓毒症难以区分）的限制。在临床前模型中，IL-2刺激血管生成素-2分泌，其增加内皮渗透性并引起肺水肿。然而，这些关系在人类中尚未完全阐明。此外，血浆血管生成素-2与器官功能的相关性尚不清楚。我们假设血浆血管生成素-2浓度在HDIL-2期间增加，并且与临床病理生理学相关。我们招募了13名接受HDIL-2治疗的转移性黑色素瘤或肾细胞癌受试者，并每天收集血液和肺功能测定数据。ELISA法测定血浆中血管生成素2和白细胞介素6的浓度。基线时，平均血管生成素-2浓度为2.5 ng/mL（SD 1.0 ng/mL）。治疗期间血管生成素-2浓度增加：倒数第二天的平均浓度为16.0 ng/mL（SD 4.5 ng/mL），在治疗的最后一天进一步增加至18.6 ng/mL（SD 4.9 ng/mL; p < 0.05 vs倒数第二天）。治疗期间，一秒用力呼气量（FEV-1）下降。有趣的是，血浆血管生成素-2浓度与FEV-1呈负相关（斯皮尔曼r=-0.78，p < 0.0001）。血浆促血管生成素-2浓度还与血浆白细胞介素-6浓度（r = 0.61，p < 0.0001）和序贯器官衰竭评估（SOFA）评分（r = 0.68，p < 0.0001）相关。血浆血管生成素-2浓度在HDIL-2给药期间增加，并与肺功能障碍相关。HDIL-2可作为脓毒症和急性肺损伤的临床模型。需要进一步调查。
The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High Dose Interleukin-2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In pre-clinical models, IL-2 stimulates angiopoietin-2 secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Further, the relevance of plasma angiopoietin-2 to organ function is not clear. We hypothesized that plasma angiopoietin-2 concentrations increase during HDIL-2, and are relevant to clinical pathophysiology. We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2, and collected blood and spirometry data daily. The plasma concentrations of angiopoietin-2 and interleukin-6 were measured with ELISA. At baseline, the mean angiopoietin-2 concentration was 2.5 ng/mL (SD 1.0 ng/mL). Angiopoietin-2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 ng/mL (SD 4.5 ng/mL) and increased further to 18.6 ng/mL (SD 4.9 ng/mL; p < 0.05 vs penultimate) during the last day of therapy. The Forced Expiratory Volume in one second (FEV-1) decreased during treatment. Interestingly, plasma angiopoietin-2 concentrations correlated negatively with FEV-1 (Spearman r=−0.78, p < 0.0001). Plasma angiopoietin-2 concentrations also correlated with plasma interleukin-6 concentrations (r = 0.61, p < 0.0001) and Sequential Organ Failure Assessment (SOFA) scores (r = 0.68, p < 0.0001). Plasma angiopoietin-2 concentrations increase during HDIL-2 administration, and correlate with pulmonary dysfunction. HDIL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.