Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Brazil.
Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children's at Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Front Immunol. 2024 Jun 25;15:1411979. doi: 10.3389/fimmu.2024.1411979. eCollection 2024.
Kawasaki disease (KD), an acute febrile illness and systemic vasculitis, is the leading cause of acquired heart disease in children in industrialized countries. KD leads to the development of coronary artery aneurysms (CAA) in affected children, which may persist for months and even years after the acute phase of the disease. There is an unmet need to characterize the immune and pathological mechanisms of the long-term complications of KD.
We examined cardiovascular complications in the cell wall extract (LCWE) mouse model of KD-like vasculitis over 4 months. The long-term immune, pathological, and functional changes occurring in cardiovascular lesions were characterized by histological examination, flow cytometric analysis, immunofluorescent staining of cardiovascular tissues, and transthoracic echocardiogram.
CAA and abdominal aorta dilations were detected up to 16 weeks following LCWE injection and initiation of acute vasculitis. We observed alterations in the composition of circulating immune cell profiles, such as increased monocyte frequencies in the acute phase of the disease and higher counts of neutrophils. We determined a positive correlation between circulating neutrophil and inflammatory monocyte counts and the severity of cardiovascular lesions early after LCWE injection. LCWE-induced KD-like vasculitis was associated with myocarditis and myocardial dysfunction, characterized by diminished ejection fraction and left ventricular remodeling, which worsened over time. We observed extensive fibrosis within the inflamed cardiac tissue early in the disease and myocardial fibrosis in later stages.
Our findings indicate that increased circulating neutrophil counts in the acute phase are a reliable predictor of cardiovascular inflammation severity in LCWE-injected mice. Furthermore, long-term cardiac complications stemming from inflammatory cell infiltrations in the aortic root and coronary arteries, myocardial dysfunction, and myocardial fibrosis persist over long periods and are still detected up to 16 weeks after LCWE injection.
川崎病（KD）是一种急性发热性疾病和全身性血管炎，是工业化国家儿童获得性心脏病的主要原因。KD 导致受影响儿童的冠状动脉瘤（CAA）的发展，这些动脉瘤在疾病的急性期后可能持续数月甚至数年。目前迫切需要描述 KD 的长期并发症的免疫和病理机制。
我们在 LCWE 小鼠 KD 样血管炎模型中观察了 4 个月的心血管并发症。通过组织学检查、流式细胞分析、心血管组织免疫荧光染色和经胸超声心动图，对心血管病变中发生的长期免疫、病理和功能变化进行了特征描述。
在 LCWE 注射和急性血管炎发作后长达 16 周，可检测到 CAA 和腹主动脉扩张。我们观察到循环免疫细胞谱组成的改变，例如在疾病的急性期单核细胞频率增加，中性粒细胞计数增加。我们确定了循环中性粒细胞和炎症性单核细胞计数与 LCWE 注射后早期心血管病变严重程度之间的正相关。LCWE 诱导的 KD 样血管炎与心肌炎和心肌功能障碍有关，其特征为射血分数降低和左心室重构，这些变化随时间恶化。我们在疾病早期观察到炎症性心脏组织内广泛的纤维化，以及后期的心肌纤维化。
我们的研究结果表明，在 LCWE 注射小鼠中，急性期循环中性粒细胞计数增加是心血管炎症严重程度的可靠预测指标。此外，源于主动脉根部和冠状动脉炎症细胞浸润、心肌功能障碍和心肌纤维化的长期心脏并发症持续存在，并在 LCWE 注射后长达 16 周仍被检测到。
