Inhibition of Necroptosis to Prevent Long-term Cardiac Damage During Pneumococcal Pneumonia and Invasive Disease
Inhibition of Necroptosis to Prevent Long-term Cardiac Damage During Pneumococcal Pneumonia and Invasive Disease
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DOI：
10.1093/infdis/jiaa295
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发表时间：
2020-12-01
影响因子：
6.4
通讯作者：
Orihuela, Carlos J.
中科院分区：
文献类型：
--
作者：
Beno, Sarah M.;Riegler, Ashleigh N.;Orihuela, Carlos J.
背景资料。肺炎链球菌感染可导致菌血症，造成包括心脏损害在内的毁灭性后果。坏死性下垂是一种细胞死亡的前炎性形式，由肺炎链球菌溶血素等致孔毒素引起。抗坏死性下垂药物可减轻侵袭性肺炎球菌病(IPD)时的器官损害。用人和小鼠心肌细胞进行了体外实验。在肺炎链球菌攻击3个月后，用高分辨率超声心动图对氨苄西林救治的小鼠的长期心脏损害进行评估。波纳替尼是一种坏死性下垂抑制药物，也是美国食品和药物管理局批准的治疗淋巴细胞性白血病的药物，它与氨苄西林一起被腹腔注射，以测试其治疗效果。心脏切片的组织学检查包括苏木精-伊红染色显示明显的损害，免疫荧光染色显示坏死性下垂，天狼星红/快速绿色染色显示胶原沉积。心肌细胞死亡和心脏损伤是由肺炎毒素介导的坏死性下垂引起的。IPD会导致长期的心脏损害，小鼠心脏中从头开始的胶原沉积和缩短率的减少就是明证。联合抑制坏死性下垂可减少急性感染小鼠心脏中肺炎链球菌的数量和血清肌钙蛋白I水平，减少胶原沉积，保护恢复期的心功能。IPD期间发生的急性和长期心脏损害部分是由于心肌细胞坏死性下垂。坏死下垂抑制剂可能是一种可行的辅助治疗方法。
Background. Streptococcus pneumoniae infection can result in bacteremia with devastating consequences including heart damage. Necroptosis is a proinflammatory form of cell death instigated by pore-forming toxins such as S. pneumoniae pneumolysin. Necroptosis-inhibiting drugs may lessen organ damage during invasive pneumococcal disease (IPD).Methods. In vitro experiments were carried out with human and mouse cardiomyocytes. Long-term cardiac damage was assessed using high-resolution echocardiography in ampicillin-rescued mice 3 months after challenge with S. pneumoniae. Ponatinib, a necroptosis-inhibiting and Food and Drug Administration-approved drug for lymphocytic leukemia treatment, was administered intraperitoneally alongside ampicillin to test its therapeutic efficacy. Histology of heart sections included hematoxylin-eosin staining for overt damage, immunofluorescence for necroptosis, and Sirius red/fast green staining for collagen deposition.Results. Cardiomyocyte death and heart damage was due to pneumolysin-mediated necroptosis. IPD leads to long-term cardiac damage, as evidenced by de novo collagen deposition in mouse hearts and a decrease in fractional shortening. Adjunct necroptosis inhibition reduced the number of S. pneumoniae foci observed in hearts of acutely infected mice and serum levels of troponin I. Ponatinib reduced collagen deposition and protected heart function in convalescence.Conclusions. Acute and long-term cardiac damage incurred during IPD is due in part to cardiomyocyte necroptosis. Necroptosis inhibitors may be a viable adjunct therapy.