Vanaudenaerde B M, De Vleeschauwer S I, Vos R, Meyts I, Bullens D M, Reynders V, Wuyts W A, Van Raemdonck D E, Dupont L J, Verleden G M
Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium.
Am J Transplant. 2008 Sep;8(9):1911-20. doi: 10.1111/j.1600-6143.2008.02321.x.
Bronchiolitis obliterans syndrome (BOS) is the leading cause of death after lung transplantation. Treatment is challenging, as the precise pathophysiology remains unclear. We hypothesize that T(H)17 lineage plays a key role in the pathophysiology of BOS by linking T-cell activation to neutrophil influx and chronic inflammation. In a cross-sectional study, bronchoalveolar lavage (BAL) samples of 132 lung transplant recipients were analyzed. Patients were divided in four groups: stable or suffering from infection (INF), acute rejection (AR) or BOS. The upstream T(H)17 skewing (TGF-beta/IL1beta/IL6/IL23), T(H)17 counteracting (IL2), T(H)17 effector cytokine (IL17) and the principal neutrophil-attracting chemokine (IL8), were quantified at the mRNA or protein level in combination with the cell profiles. The BOS group (n = 36) showed an increase in IL1beta protein (x1.5), IL6 protein (x3), transforming growth factor-beta (TGF-beta) mRNA (x3), IL17 mRNA (x20), IL23 mRNA (x10), IL8 protein (x2), IL8 mRNA (x3) and a decrease in IL2 protein (x0.8). The infection group (n = 11) demonstrated an increase in IL1beta protein (x5), IL6 protein (x20), TGF-beta mRNA (x10), IL17 mRNA (x300), IL23 mRNA (x200) and IL8 protein (x6). The acute rejection group (n = 43) only revealed an increase in IL6 protein (x6) and IL8 protein (x2) and a decrease in IL2 protein (x0.7). Lymphocytes and neutrophils were increased in all groups compared to the stable (n = 42). Our findings demonstrate the IL23/IL17 axis to be involved in the pathophysiology of BOS potentially triggering the IL8-mediated neutrophilia. IL6, IL1beta and IL23 seem to be skewing cytokines and IL2 a counteracting cytokine for T(H)17 alignment. The involvement of TGF-beta could not be confirmed, either as T(H)17 steering or as counteracting cytokine.
闭塞性细支气管炎综合征（BOS）是肺移植后死亡的主要原因。由于其确切的病理生理学仍不清楚，治疗颇具挑战性。我们推测辅助性T细胞17（T(H)17）谱系通过将T细胞激活与中性粒细胞流入和慢性炎症联系起来，在BOS的病理生理学中起关键作用。在一项横断面研究中，分析了132名肺移植受者的支气管肺泡灌洗（BAL）样本。患者分为四组：病情稳定或患有感染（INF）、急性排斥反应（AR）或BOS。结合细胞图谱，在mRNA或蛋白质水平对上游T(H)17偏斜（转化生长因子-β/TGF-β/白细胞介素1β/IL1β/白细胞介素6/IL6/白细胞介素23/IL23）、T(H)17拮抗（白细胞介素2/IL2）、T(H)17效应细胞因子（白细胞介素17/IL17）和主要的中性粒细胞趋化因子（白细胞介素8/IL8）进行了定量分析。BOS组（n = 36）显示白细胞介素1β蛋白增加（1.5倍）、白细胞介素6蛋白增加（3倍）及转化生长因子-β（TGF-β）mRNA增加（3倍）、白细胞介素17 mRNA增加（20倍）、白细胞介素23 mRNA增加（10倍）、白细胞介素8蛋白增加（2倍）、白细胞介素8 mRNA增加（3倍）以及白细胞介素2蛋白减少（0.8倍）。感染组（n = 11）显示白细胞介素1β蛋白增加（5倍）、白细胞介素6蛋白增加（20倍）、TGF-β mRNA增加（10倍）、白细胞介素17 mRNA增加（300倍）、白细胞介素23 mRNA增加（200倍）以及白细胞介素8蛋白增加（6倍）。急性排斥反应组（n = 43）仅显示白细胞介素6蛋白增加（6倍）和白细胞介素8蛋白增加（2倍）以及白细胞介素2蛋白减少（0.7倍）。与病情稳定组（n = 42）相比，所有组的淋巴细胞和中性粒细胞均增加。我们的研究结果表明，白细胞介素23/白细胞介素17轴参与了BOS的病理生理学过程，可能触发白细胞介素8介导的中性粒细胞增多。白细胞介素6、白细胞介素1β和白细胞介素23似乎是T(H)17偏斜细胞因子，而白细胞介素2是T(H)17排列的拮抗细胞因子。无法确定转化生长因子-β作为T(H)17导向或拮抗细胞因子的作用。
