Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis.
Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis.
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DOI：
10.3389/fphar.2016.00183
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发表时间：
2016
影响因子：
5.6
通讯作者：
Kirschner DE
中科院分区：
文献类型：
--
作者：
Warsinske HC;Wheaton AK;Kim KK;Linderman JJ;Moore BB;Kirschner DE
肺纤维化是肺组织的病理性重塑，可导致呼吸困难、生活质量下降和患者预后不良。纤维化是肺组织损伤的结果，尽管这种反应的机制还没有很好地表征。该疾病的部分驱动因素是成纤维细胞增殖和向肌成纤维细胞分化的失调，以及促纤维化介质驱动的上皮细胞凋亡。最明确的与肺纤维化相关的促纤维化介质是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生产不足和敏感性被认为是促使成纤维细胞积累的原因。现有的治疗既不能停止也不能逆转肺损伤。在这项研究中，我们有两个目的：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多尺度混合剂的计算模型结合起来，该模型描述了共培养中的成纤维细胞和上皮细胞。在这个模型中，TGF-β1代表了促纤维化介质，我们包括了成纤维细胞中TGF-β1受体配体信号传导的详细动力学。PGE2是一种抗纤维化介质。通过不确定性和敏感性分析，我们确定了TGF-β1合成、TGF-β1激活和PGE2合成是导致纤维化结局的关键机制。我们进一步证明，结合针对成纤维细胞调节和上皮细胞存活的潜在治疗的干预策略比单独的策略更能促进健康的组织修复。现有药物和化合物的联合可能会显著改善目前肺纤维化的护理标准。因此，双重打击治疗干预策略可能被证明是必要的，以停止和扭转疾病动态。
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.