Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany.
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany; Institute of Pathology, Hannover Medical School, Hannover, Germany.
Am J Pathol. 2022 Aug;192(8):1110-1121. doi: 10.1016/j.ajpath.2022.05.004. Epub 2022 May 29.
Alveolar capillary dysplasia (ACD) is a rare lung developmental disorder leading to persistent pulmonary arterial hypertension and fatal outcomes in newborns. The current study analyzed the microvascular morphology and the underlying molecular background of ACD. One ACD group (n = 7), one pulmonary arterial hypertension group (n = 20), and one healthy con1trol group (n = 16) were generated. Samples of histologically confirmed ACD were examined by exome sequencing and array-based comparative genomic hybridization. Vascular morphology was analyzed using scanning electron microscopy of microvascular corrosion casts. Gene expression and biological pathways were analyzed using two panels on inflammation/kinase-specific genes and a comparison analysis tool. Compartment-specific protein expression was analyzed using immunostaining. In ACD, there was an altered capillary network, a high prevalence of intussusceptive angiogenesis, and increased activity of C-X-C motif chemokine receptor 4 (CXCR4), hypoxia-inducible factor 1α (HIF1A), and angiopoietin signaling pathways compared with pulmonary arterial hypertension/healthy controls. Histologically, there was a markedly increased prevalence of endothelial tyrosine kinase receptor (TEK/TIE2) macrophages in ACD, compared with the other groups, whereas the CXCR4 ligand CXCL12 and HIF1A showed high expression in all groups. ACD is characterized by dysfunctional capillaries and a high prevalence of intussusceptive angiogenesis. The results indicate that endothelial CXCR4, HIF1A, and angiopoietin signaling as well as TIE2 macrophages are crucial for the induction of intussusceptive angiogenesis and vascular remodeling. Future studies should address the use of anti-angiogenic agents in ACD, where TIE2 appears as a promising target.
肺泡毛细血管发育不良（ACD）是一种罕见的肺部发育障碍，可导致新生儿持续性肺动脉高压和致命结局。本研究分析了 ACD 的微血管形态和潜在的分子背景。ACD 组（n=7）、肺动脉高压组（n=20）和健康对照组（n=16）各一组。通过外显子组测序和基于阵列的比较基因组杂交对组织学证实的 ACD 样本进行了分析。使用微血管腐蚀铸件的扫描电子显微镜分析了血管形态。使用炎症/激酶特异性基因的两个面板和比较分析工具分析了基因表达和生物学途径。使用免疫染色分析了特定隔室的蛋白表达。与肺动脉高压/健康对照组相比，ACD 存在毛细血管网络改变、丛状血管生成高发以及 C-X-C 基序趋化因子受体 4（CXCR4）、缺氧诱导因子 1α（HIF1A）和血管生成素信号通路活性增加。组织学上，与其他组相比，ACD 中内皮酪氨酸激酶受体（TEK/TIE2）巨噬细胞的发生率明显增加，而 CXCR4 配体 CXCL12 和 HIF1A 在所有组中均表现出高表达。ACD 的特征是毛细血管功能障碍和丛状血管生成高发。结果表明，内皮 CXCR4、HIF1A 和血管生成素信号以及 TIE2 巨噬细胞对于诱导丛状血管生成和血管重塑至关重要。未来的研究应该探讨在 ACD 中使用抗血管生成药物，其中 TIE2 似乎是一个很有前途的靶点。
