Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Clin Transl Sci. 2021 Mar;14(2):518-528. doi: 10.1111/cts.12899. Epub 2020 Oct 27.
Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.
肠道血管扩张症（AEC）反复急性出血对临床干预提出了重大挑战。目前的治疗方法是经验性的，临床效果往往不佳。对这些病变病理生理学的认识的提高将有助于指导治疗。我们使用美国食品和药物管理局（FDA）不良事件报告系统（FAERS）的数据，分析了 1200 万例患者报告，以确定与胃肠道出血呈负相关并可能限制 AEC 严重程度的药物。FAERS 分析显示，用于糖尿病患者的药物和针对 PPARγ 相关机制的药物与减少 AEC 表型相关（P < 0.0001）。分析了辛辛那提大学医院的电子健康记录（EHR）以验证 FAERS 分析。EHR 数据显示，PPARγ 激动剂治疗的患者 AEC 风险和相关表型降低了 5.6%。用于 AEC 表型的小鼠基因敲除模型用于构建候选药物靶点和途径的基因调控网络，该网络表明伤口愈合、血管发育和氧化应激调节在 AEC 病理生理学中受到影响。检查了人类结肠组织中关键途径蛋白（PPARγ、HIF1α、VEGF 和 TGFβ1）的表达差异。体外分析人 AEC 组织显示 PPARγ 和 TGFβ1 的表达低于对照（0.55 ± 0.07 和 0.49 ± 0.05）。分析了国家生物技术信息中心（NCBI）基因表达综合数据库（GEO）RNA-Seq 数据以证实人类组织发现。这种关键基因表达改变的综合发现涉及氧化应激和损伤修复机制，为 AEC 病因学提供了新的见解，这将改善针对 AEC 的机制研究和更优化的医学治疗。
