Brook, B. S. | Search bioRxiv

bioRxiv2022

Differential remodelling in small and large murine airways revealed by novel whole lung airway analysis.

Airway remodelling occurs in chronic asthma leading to increased airway smooth muscle (ASM) mass and extra-cellular matrix (ECM) deposition. Whilst extensively studied in murine airways; studies report only selected larger airways at one time point meaning the spatial distribution and resolution of remodelling are poorly understood. Here we use a new method allowing comprehensive assessment of the spatial and temporal changes in ASM, ECM and epithelium in large numbers of murine airways after allergen challenge. Using image processing to analyse 20-50 airways from a whole lung section revealed increases in ASM and ECM after allergen challenge were greater in small and large rather than intermediate airways. ASM predominantly accumulated adjacent to the basement membrane whereas ECM was distributed across the airway wall. Epithelial hyperplasia was most marked in small and intermediate airways. Post challenge, ASM changes resolved over seven days whereas ECM and epithelial changes persisted. The new method suggests large and small airways remodel differently and the long-term consequences of airway inflammation may depend more on ECM and epithelial changes than ASM. The method reduces the number of animals needed, reveals important spatial differences in remodelling and could set new analysis standards for murine asthma models.

physiology↗

bioRxiv2021

A dynamical model of TGF-β activation in asthmatic airways

Excessive activation of the regulatory cytokine transforming growth factor {beta} (TGF-{beta}) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-{beta}. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-{beta} concentration, with the latter leading additionally to increased ASM and ECM density. We associate the former with a healthy homeostatic state and the latter with a diseased (asthmatic) state. We demonstrate that external stimuli, inducing TGF-{beta} activation via ASM contraction (mimicking an asthmatic exacerbation), can perturb the system irreversibly from the healthy state to the diseased one. We show that the properties of the stimuli, such as their frequency or strength, and the clearance of surplus active TGF-{beta}, are important in determining the long-term dynamics and the development of disease. Finally we demonstrate the utility of this model in investigating temporal responses to bronchial thermoplasty, a therapeutic intervention in which ASM is ablated by applying thermal energy to the airway wall. The model predicts the parameter-dependent threshold damage required to obtain irreversible reduction in ASM content suggesting that certain asthma phenotypes are more likely to benefit from this intervention.

systems biology↗