Unit of Lung Biology, Dept. of Experimental Medical Science, Lund University, Sweden.
Unit of Lung Biology, Dept. of Experimental Medical Science, Lund University, Sweden.
Respir Med. 2020 May;166:105944. doi: 10.1016/j.rmed.2020.105944. Epub 2020 Mar 21.
Chronic lung allograft dysfunction including Bronchiolitis obliterans syndrome (BOS) is common after lung transplantation. Histologically, BOS is recognized as fibrotic lesions with accumulated extracellular matrix (ECM) in small airways. Lung fibroblasts are major producers of ECM and vascular endothelial growth factor (VEGF). In this study we hypothesize that VEGF is involved in BOS development after lung transplantation.
We investigated the effect of profibrotic transforming growth factor (TGF-β) on VEGF synthesis in lung fibroblasts isolated from distal lung tissue biopsies taken from patients at 3, 6 and 12 months after lung transplantation (n = 14). Co-expression of VEGF receptor (VEGFR) 2 and collagen marker prolyl4-hydroxylase (p4OH) were analyzed in lung tissue from patients with BOS (n = 11).
VEGF synthesis from distal derived lung fibroblasts were significantly lower 3 months after lung transplantation (168.6 ± 133.7; n = 7) compared to non-transplanted subjects (451.8 ± 185.9; n = 9; p = 0.0033) and increased over time at 6 months (584.1 ± 264.9; n = 9; p = 0.0033) and 12 months (451.1 ± 207.5; n = 8; p = 0.0065) post transplantation. TGF-β significantly induced VEGF synthesis at all time points. At 12 months post transplantation there was significantly less VEGF synthesis after TGF-β stimulation in fibroblasts obtained from BOS patients (1170 ± 450.2; n = 4) compared to patients without any chronic rejection process (1980 ± 417.9; n = 4; p < 0.039). The numbers of cells expressing VEGFR2/p4OH were increased in patients with BOS (33.2 ± 10.9; n = 11) compared to control subjects (10.1 ± 9.9; n = 11; p < 0.001).
Our results support that changes in VEGF/VEGFR2 axis could be involved in BOS development and marker of poor outcome.
慢性肺移植物功能障碍包括闭塞性细支气管炎综合征（BOS）是肺移植后的常见并发症。从组织学上看，BOS 被认为是小气道中累积细胞外基质（ECM）的纤维化病变。肺成纤维细胞是 ECM 和血管内皮生长因子（VEGF）的主要产生者。在这项研究中，我们假设 VEGF 参与了肺移植后的 BOS 发展。
我们研究了纤维化转化生长因子（TGF-β）对肺移植后 3、6 和 12 个月时取自患者远端肺组织活检的肺成纤维细胞中 VEGF 合成的影响（n=14）。分析了 BOS 患者肺组织中 VEGF 受体（VEGFR）2 和胶原蛋白标记脯氨酰 4-羟化酶（p4OH）的共表达（n=11）。
肺移植后 3 个月时，来自远端肺来源的成纤维细胞的 VEGF 合成明显低于未移植患者（168.6±133.7；n=7）（451.8±185.9；n=9；p=0.0033），并随时间推移在 6 个月（584.1±264.9；n=9；p=0.0033）和 12 个月（451.1±207.5；n=8；p=0.0065）时增加。TGF-β 在所有时间点都显著诱导了 VEGF 的合成。肺移植后 12 个月，BOS 患者的成纤维细胞在 TGF-β 刺激后 VEGF 合成明显减少（1170±450.2；n=4），而无任何慢性排斥过程的患者则明显增加（1980±417.9；n=4；p<0.039）。BOS 患者表达 VEGFR2/p4OH 的细胞数量（33.2±10.9；n=11）明显高于对照组（10.1±9.9；n=11；p<0.001）。
我们的研究结果支持 VEGF/VEGFR2 轴的变化可能参与 BOS 的发展和预后不良的标志物。
