PDF(Pubmed)
Abstract：
The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.
摘要：
成年哺乳动物心脏具有有限的内源性再生能力,并且通过最终导致瘢痕形成的炎症和纤维化级联的激活而愈合。梗塞后,大量心肌细胞死亡释放了广泛的损伤相关分子模式,引发心肌和全身炎症反应.TLRs(toll样受体)和NLRs(NOD样受体)识别损伤相关分子模式(DAMPs)并转导下游促炎信号,导致细胞因子上调（如白细胞介素-1，TNF-α[肿瘤坏死因子-α]，和白细胞介素-6）和趋化因子（如CCL2[CC趋化因子配体2]）和中性粒细胞的募集，单核细胞,和淋巴细胞。梗死心脏中心脏巨噬细胞的扩增和多样化在从死细胞清除梗死和随后刺激修复途径中起主要作用。Efferocytosis触发抗炎介质的诱导和释放，抑制炎症反应并为修复性成纤维细胞和血管细胞的活化奠定基础。生长因子介导的途径，神经体液级联，和沉积在临时基质中的基质细胞蛋白刺激成纤维细胞活化和增殖以及肌成纤维细胞转化。良好组织的基于胶原的细胞外基质网络的沉积保护心脏免受灾难性破裂并减弱心室扩张。瘢痕成熟需要刺激抑制成纤维细胞活性并防止过度纤维化的内源性信号。此外，在成熟的疤痕中，梗死新生血管获得壁细胞涂层，有助于微血管网络的稳定。过度,延长,或失调的炎症或纤维化级联反应加剧了不良的重塑和功能障碍。此外，炎性白细胞和成纤维细胞可导致心律失常发生。炎症和纤维化途径可能是减轻心肌梗死患者心力衰竭进展和抑制心律失常发生的有希望的治疗靶点。
