Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA.
J Physiol. 2023 Jul;601(13):2635-2654. doi: 10.1113/JP283346. Epub 2022 Aug 8.
After myocardial infarction (MI), cardiac cells work together to regulate wound healing of the infarct. The pathological response to MI yields cardiac remodelling comprising inflammatory and fibrosis phases, and the interplay of cellular dynamics that underlies these phases has not been elucidated. This study developed a computational model to identify cytokine and cellular dynamics post-MI to predict mechanisms driving post-MI inflammation, resolution of inflammation, and scar formation. Additionally, this study evaluated the interdependence between inflammation and fibrosis. Our model bypassed limitations of in vivo approaches in achieving cellular specificity and performing specific perturbations such as global knockouts of chemical factors. The model predicted that inflammation is a graded response to initial infarct size that is amplified by a positive feedback loop between neutrophils and interleukin 1β (IL-1β). Resolution of inflammation was driven by degradation of IL-1β, matrix metalloproteinase 9, and transforming growth factor β (TGF-β), as well as apoptosis of neutrophils. Inflammation regulated TGFβ secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Lastly, we found that mature collagen deposition was an ultrasensitive switch in response to inflammation, which was amplified primarily by cardiac fibroblast proliferation. These findings describe the relationship between inflammation and fibrosis and highlight how the two responses work together post-MI. This model revealed that post-MI inflammation and fibrosis are dynamically coupled, which provides rationale for designing novel anti-inflammatory, pro-resolving or anti-fibrotic therapies that may improve the response to MI. KEY POINTS: Inflammation and matrix remodelling are two processes involved in wound healing after a heart attack. Cardiac cells work together to facilitate these processes; this is done by secreting cytokines that then regulate the cells themselves or other cells surrounding them. This study developed a computational model of the dynamics of cardiac cells and cytokines to predict mechanisms through which inflammation and matrix remodelling is regulated. We show the roles of various cytokines and signalling motifs in driving inflammation, resolution of inflammation and fibrosis. The novel concept of inflammation-fibrosis coupling, based on the model prediction that inflammation and fibrosis are dynamically coupled, provides rationale for future studies and for designing therapeutics to improve the response after a heart attack.
心肌梗死后（MI），心脏细胞共同作用以调节梗死的伤口愈合。MI 的病理反应产生包含炎症和纤维化阶段的心脏重塑，并且这些阶段下细胞动态的相互作用尚未阐明。本研究开发了一种计算模型来识别 MI 后细胞因子和细胞动态，以预测驱动 MI 后炎症、炎症消退和瘢痕形成的机制。此外，本研究评估了炎症和纤维化之间的相互依存关系。我们的模型克服了体内方法在实现细胞特异性和进行特定扰动方面的局限性，例如化学因子的全局敲除。该模型预测炎症是对初始梗死面积的分级反应，通过中性粒细胞和白细胞介素 1β（IL-1β）之间的正反馈循环放大。炎症消退是由 IL-1β、基质金属蛋白酶 9 和转化生长因子 β（TGF-β）的降解以及中性粒细胞的凋亡驱动的。炎症通过免疫细胞募集和巨噬细胞吞噬作用的上调来直接调节 TGFβ 的分泌。最后，我们发现成熟胶原沉积是对炎症的超敏开关，主要通过心脏成纤维细胞的增殖放大。这些发现描述了炎症和纤维化之间的关系，并强调了这两种反应在 MI 后如何协同作用。该模型揭示了 MI 后炎症和纤维化是动态耦合的，这为设计新型抗炎、促消退或抗纤维化疗法提供了依据，这些疗法可能改善对 MI 的反应。关键点：炎症和基质重塑是心脏病发作后伤口愈合过程中的两个过程。心脏细胞共同作用以促进这些过程；这是通过分泌细胞因子来完成的，这些细胞因子然后调节自身细胞或周围的其他细胞。本研究开发了一种心脏细胞和细胞因子动力学的计算模型，以预测调节炎症和基质重塑的机制。我们展示了各种细胞因子和信号模式在驱动炎症、炎症消退和纤维化中的作用。基于模型预测炎症和纤维化是动态耦合的新概念，为未来的研究和设计改善心脏病发作后反应的治疗方法提供了依据。
