山口医学

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山口医学 Volume 70 Issue 2
published_at 2021-05-13

Sterile inflammation as a novel therapeutic target to heart failure

心不全の新たな治療標的としての自然炎症
Suetomi Takeshi
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B030070000201.pdf
Descriptions
高齢化に伴い本邦の心不全患者は今後もしばらく増加するとみられている.かたやその治療法については大半が対症療法にとどまっており,心不全の病態に根本的にアプローチする治療が求められている.そのような中,最近の大規模臨床試験の結果から,心機能低下に自然炎症が関与しているという既知の事実が再び注目されている.自然炎症は損傷組織由来の成分(dampS)の認識により引き起こされるほか,細胞損傷がみられない段階においても,カルシウム調節因子の異常等に伴い心筋細胞内の炎症遺伝子およびnlrp3インフラマソームの活性化を経てもたらされ,その後の炎症性細胞の浸潤や心筋線維化,心機能低下につながることが示されている.自然炎症と慢性心不全の関係が明らかになることで,炎症シグナルの選択的制御が新たな治療標的として期待される.
There is substantial evidence that chronic heart failure is associated with inflammation. Ischemic stress such as myocardial infarction lead to necrotic cell death and release of damage associated molecular patterns(DAMPs),factors that signal cell damage and induce expression of proinflammatory chemokines and cytokines. It has recently become evident that nonischemic interventions are also associated with increases in inflammatory genes and immune cell accumulation in the heart and that these contribute to fibrosis and ventricular dysfunction. In this review we provide recent evidence of adverse cardiac remodeling induced by sterile inflammation in response to nonischemic stress. We also introduce the role of the multifunctional Ca^{2+} /calmodulin-dependent protein kinase, CaMKII, as a transducer of stress signals to nuclear factor-B activation, expression of proinflammatory cytokines and chemokines, and priming and activation of the NOD-like pyrin domain-containing protein 3(NLRP3)inflammasome in cardiomyocytes. The potential efficacy of anti-inflammatory therapy was shown by the results of the recently published clinical trials in which a significant decrease in adverse cardiac events was observed in patients treated by inhibitions of mediators generated through the NLRP3 inflammasome, suggesting that the inflammasome plays a central role in both initiating and sustaining cardiac sterile inflammation. Achieving a further understanding of these mechanisms has implications for the development of therapeutic regimens to limit cardiac remodeling.
Creator Keywords
心不全
心リモデリング
慢性炎症
自然免疫
心筋線維化