Investigating small airway closure in the human lung using multi scale approaches

Lung airways have a branched structure, with increasingly smaller branches proceeding down up to 25 generations. The smallest (acinar) airways (beyond generation 10) are not well understood, as they are too small to be seen in CT scans and consequently are typically absent from whole lung models. However, the importance of these small airways is increasingly being recognized as central to the pathogenesis of common obstructive lung diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

An important problem in lung diseases such as asthma and COPD is remodelling and closure of the small airways (which can occur catastrophically). Airway closure and remodelling are associated with a variety of important disease features such as asthma attacks (closure) and chronic persistent disease and lung function decline (remodelling). However understanding how these events link to physiological outcomes on a patient specific basis requires coupling of micro scale and macro scale (whole organ) models.

This programme of work has three strands. Dr. Alkiviadis Tsamis will lead work on tissue computational modelling of lung small airway remodelling (variation in geometry and material properties) and closure using tissue biomechanics techniques previously applied in similar tubular tubular structures such as small diameter vessels. The computational simulation results will be validated using state-of-the-art microcontact printing and biomimetic microfabrication technologies. Dr. Simon Gill will provide his expertise on mathematical modelling aspects of simplified analytical models and incorporation of small airway model into whole human lung simulation. Patient-specific microstructural input parameters needed for the computational and analytical airway tissue models of Dr. Tsamis and Dr. Gill will be informed by integrated image registration analysis of CT and histology data in asthma patients, which will be led by Prof. Salman Siddiqui. Preliminary microstructural input data has already been generated. Moreover, Prof. Siddiqui will lead work on generation of data on airway surfactant properties via analysis of a novel airway surface liquid matrix (particles in exhaled air) to measure surface energy, which is the driving force for closure of the small airway. Furthermore, Prof. Siddiqui will be able to provide constructive feedback on the whole lung test conditions and interpretation of the computational simulation results based on his clinical expertise.
This work is a genuine collaboration, which is already the subject of a joint paper in preparation by Dr. Gill and Prof. Siddiqui. This paper develops a model for airway closure in a highly idealised situation. The programme of work proposed here is the next step in a new collaboration to be led by Dr. Tsamis. The intention is to extend this abstract model to actual acinar airways based on quantified geometric and physical data. The overall aim of this project is to incorporate this small airway closure model into a whole lung model. The whole lung model has been developed through an EU Framework Funded Project (Bordas R et al, PLos One 2016), led by Prof. Siddiqui, although the model currently terminates at the 10th generation airways, and hence does not include the small airways which are the focus of this project.