Calprotectin blockade inhibits long-term vascular pathology following peritoneal dialysis-associated bacterial infection.
Calprotectin blockade inhibits long-term vascular pathology following peritoneal dialysis-associated bacterial infection.
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DOI：
10.3389/fcimb.2023.1285193
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发表时间：
2023
影响因子：
5.7
通讯作者：
Raby, Anne-Catherine
中科院分区：
文献类型：
--
作者：
Cetin, Esra;Mazzarino, Morgane;Gonzalez-Mateo, Guadalupe T.;Kopytina, Valeria;Meran, Soma;Fraser, Donald;Lopez-Cabrera, Manuel;Labeta, Mario O.;Raby, Anne-Catherine
关键词：
细菌感染和并发炎症与长期心血管（CV）风险增加相关。在接受腹膜透析（PD）的患者中，细菌性腹膜炎是常见事件，每次发作都会进一步增加晚期CV死亡风险。然而，在开发安全有效的抗炎干预措施之前，其潜在机制仍有待阐明。损伤相关分子模式（DAMP）已被证明有助于对感染的急性炎症反应，但尚未研究DAMP在PD感染消退后介导长期血管炎症和CV风险中的潜在作用。我们发现，在24小时内消退的小鼠细菌性腹膜炎导致CV疾病促进全身和血管免疫介导的炎症反应，并维持长达28天。这些包括较高的血液比例的炎性白细胞显示增加粘附分子表达，较高的血浆细胞因子水平，增加主动脉炎性和动脉粥样硬化相关基因表达。在感染的肾病小鼠中也观察到这些效应，并在常规暴露于PD液的小鼠中放大。腹膜炎发作导致PD患者和小鼠中DAMP钙卫蛋白的血浆水平升高，其中该升高维持长达28天。在体外，感染细胞培养上清液促进关键炎症和动脉粥样硬化相关细胞反应（如单核细胞趋化性和泡沫细胞形成）的能力是钙卫蛋白依赖性的。在体内，钙卫蛋白阻断剂可有力地抑制腹膜炎的短期和长期外周和血管后果，从而证明靶向DAMP钙卫蛋白是一种有前景的治疗策略，可减少感染（尤其是PD相关腹膜炎）的长期血管炎症后果，最终降低CV风险。
Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases late CV mortality risk. However, the underlying mechanism(s) remains to be elucidated before safe and efficient anti-inflammatory interventions can be developed. Damage-Associated Molecular Patterns (DAMPs) have been shown to contribute to the acute inflammatory response to infections, but a potential role for DAMPs in mediating long-term vascular inflammation and CV risk following infection resolution in PD, has not been investigated. We found that bacterial peritonitis in mice that resolved within 24h led to CV disease-promoting systemic and vascular immune-mediated inflammatory responses that were maintained up to 28 days. These included higher blood proportions of inflammatory leukocytes displaying increased adhesion molecule expression, higher plasma cytokines levels, and increased aortic inflammatory and atherosclerosis-associated gene expression. These effects were also observed in infected nephropathic mice and amplified in mice routinely exposed to PD fluids. A peritonitis episode resulted in elevated plasma levels of the DAMP Calprotectin, both in PD patients and mice, here the increase was maintained up to 28 days. In vitro, the ability of culture supernatants from infected cells to promote key inflammatory and atherosclerosis-associated cellular responses, such as monocyte chemotaxis, and foam cell formation, was Calprotectin-dependent. In vivo, Calprotectin blockade robustly inhibited the short and long-term peripheral and vascular consequences of peritonitis, thereby demonstrating that targeting of the DAMP Calprotectin is a promising therapeutic strategy to reduce the long-lasting vascular inflammatory aftermath of an infection, notably PD-associated peritonitis, ultimately lowering CV risk.
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DOI：
10.1039/c8mt00133b
发表时间：
2018-12-12
期刊：
Metallomics : integrated biometal science
影响因子：
--
作者：
Besold AN;Culbertson EM;Nam L;Hobbs RP;Boyko A;Maxwell CN;Chazin WJ;Marques AR;Culotta VC
通讯作者：
Culotta VC
影响因子：
13.2
作者：
Finkelstein, ES;Jekel, J;Bia, FJ
通讯作者：
Bia, FJ
影响因子：
2.4
作者：
Bouchareychas L;Raffai RL
通讯作者：
Raffai RL
影响因子：
6.1
作者：
Anding, K;Gross, P;Jacobs, E
通讯作者：
Jacobs, E
影响因子：
5.3
作者：
Yan, Ling;Bjork, Per;Butuc, Radu;Gawdzik, Joseph;Earley, Judy;Kim, Gene;Bowman, Marion A. Hofmann
通讯作者：
Bowman, Marion A. Hofmann