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首页> 美国卫生研究院文献>Frontiers in Pharmacology >Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis
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Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis

机译：计算模型预测成纤维细胞和上皮细胞的同时靶向是治疗肺纤维化所必需的

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Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.
机译：肺纤维化是肺组织的病理重塑，可能导致呼吸困难，生活质量下降和患者预后不良。纤维化是由于对肺组织的伤害而发生的，尽管这种反应的机制尚不十分清楚。该疾病部分是由成纤维细胞增殖和分化成肌成纤维细胞的失调以及促纤维化介质驱动的上皮细胞凋亡所驱动。与肺纤维化相关的特征最明确的促纤维化介质是TGF-β1。促纤维化介质的过度合成和敏感性，以及抗纤维化介质的产生不足和对抗纤维化介质的敏感性被认为能够使成纤维细胞积聚。可用的治疗既不能停止也不能扭转肺损伤。在这项研究中，我们有两个目标：确定在纤维化背景下驱动成纤维细胞增殖和分化以及上皮细胞存活的分子和细胞尺度机制，并预测治疗靶点和策略。我们将体外研究与基于成纤维细胞和上皮细胞共培养的基于混合试剂的多尺度计算模型相结合。在该模型中，TGF-β1代表促纤维化介质，我们包括成纤维细胞中TGF-β1受体配体信号传导的详细动态。 PGE2代表抗纤维化介质。通过不确定性和敏感性分析，我们确定了TGF-β1合成，TGF-β1活化和PGE2合成是促成纤维化结局的关键机制之一。我们进一步证明，结合针对成纤维细胞调节和上皮细胞生存的潜在疗法的干预策略可以比单独策略更好地促进健康的组织修复。现有药物和化合物的组合可能会大大改善当前的肺纤维化护理标准。因此，两次打击的治疗干预策略可能证明对阻止和逆转疾病动态是必要的。

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