A Computational Based Approach Linking Spatial and Temporal Pattern Stiffness to Decreased Lung Function in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of unknown etiology that is characterized by the histopathological pattern of usual interstitial pneumonia. The pathogenic mechanisms that regulate the activation, differentiation, and proliferation of fibroblast have been at the central stage of efforts to understand the biological pathway that drives the fibrotic process. Despite the extensive knowledge on the pathogenesis of IPF, the mechanical dysfunction associated with the remodeling of the lung tissue is still not fully understood. This study developed a computational based approach to study the pulmonary mechanics of a hexagonal lattice network of alveoli-like structures to improve understand of the mechanical properties of the lung. A dynamic probabilistic representation of a closed two-dimensional elastic model of nodes and springs was constructed from a baseline High Resolution Computed Topography (HRCT) IPF image. The progressive development of fibrosis was reconstructed from early to late-stage representations of IPF images. Given a predefined probability, regional collagen deposition was simulated by increasing random isolated lesions of the alveolar wall, represented by springs in the lattice model. The local onset of fibrosis was initialized by stiffening springs along a strain-dependent random walk to account for excess deposition of extracellular matrix and tissue remodeling as the lung deviates from its normal geometry. The regional deposition of collagen and the local manifestation of fibrosis were represented by increasing the elastic constant of the spring at the site of initiation and springs along a strain dependent random walk of length N, by a factor of 100. The value of N representing the maximum distance the spread of fibrosis was allowed to travel from its initiation site in the network model. After each expansion and contraction, the nodes were allowed to move in the direction of the applied force, while the total spring energy of the network was minimized. The cycle was repeated until all the springs k constants in the network model were increased. This study focused on modeling and analyzing various functions of the lung, and its parameters to construct a novel approach to recreate early to late-stagecross sectional representations of IPF. The model was proven to show that the onset of fibrosis tends not to follow a linear path, but establishes a sharp increase in energy as the lung structure reaches a critical threshold. The shift in slope as the concentration of spring stiffness increased was broken down into three distinct regions, < 25% (early onset), ≥ 25% and ≤ 75% (progressive), and > 75% (late stage) of the disease. This study provided a new approach to examining how pulmonary mechanics and spatial orientation of lung tissue affects the progression of IPF, and developed a framework to model other biological systems.