Israel Ethan, Hall Joseph K, Deng Yuqing, Bates Jason H T, Suki Béla
Department of Biomedical Engineering, Boston University, Boston, MA, United States.
Department of Mechanical Engineering, Boston University, Boston, MA, United States.
Front Netw Physiol. 2025 Jul 25;5:1589216. doi: 10.3389/fnetp.2025.1589216. eCollection 2025.
Pulmonary fibrosis (PF) is a heterogeneous progressive lung disease characterized by excessive extracellular matrix (ECM) deposition and cross-linking, leading to irreversible tissue stiffening and loss of function. Previous evidence suggests that percolation behavior, where increasing local stiffness facilitates the emergence of stiff regions that span the tissue, underlies the stiffening of the ECM and drives the irreversible mechanical dysfunction. However, it is not fully understood how percolation emerges from the complex interactions between cells and the ECM.
In this study, we investigated a previously published agent-based spring network model of PF that exhibited bifurcation behavior between healing and fully developed fibrosis as network members were gradually stiffened. By systematically analyzing the configuration of the initial tissue injury, we identify key structural determinants that govern whether an injury heals or transitions into fibrosis.
Results demonstrate that fibrosis is strongly associated with increased initial clustering of injured springs, reduced intercluster distances, and the presence of critical stiffening sites, or hotspots, that act as bifurcation points for disease progression. Furthermore, we show that selectively modifying the stiffness of pivotal network regions at the time of injury can shift the network's trajectory from fibrosis to healing, highlighting potential intervention targets. These findings suggest that the network structure of tissue injury may serve as a predictive marker for fibrosis susceptibility and provide a mechanistic basis for understanding the nonlinear progression of PF.
肺纤维化（PF）是一种异质性进行性肺部疾病，其特征是细胞外基质（ECM）过度沉积和交联，导致不可逆的组织硬化和功能丧失。先前的证据表明，渗流行为，即局部硬度增加促进跨越组织的硬区域出现，是ECM硬化的基础，并驱动不可逆的机械功能障碍。然而，细胞与ECM之间复杂相互作用如何产生渗流尚未完全清楚。
在本研究中，我们研究了一个先前发表的基于主体的PF弹簧网络模型，该模型在网络成员逐渐变硬时表现出愈合与完全发展的纤维化之间的分叉行为。通过系统分析初始组织损伤的构型，我们确定了决定损伤是愈合还是转变为纤维化的关键结构决定因素。
结果表明，纤维化与受伤弹簧初始聚类增加、簇间距离减小以及作为疾病进展分叉点的关键硬化部位（即热点）的存在密切相关。此外，我们表明，在损伤时选择性地改变关键网络区域的硬度可以使网络轨迹从纤维化转变为愈合，突出了潜在的干预靶点。这些发现表明，组织损伤的网络结构可能作为纤维化易感性的预测标志物，并为理解PF的非线性进展提供机制基础。
