Mathematical modelling of airway smooth muscle cell proliferation and apoptosis in asthma

A problem presented at the UK MMSG Reading 2011.

Presented by:
Dr Charlotte Billington (Division of Therapeutics & Molecular Medicine, University of Nottingham)
Prof Ian Hall (Therapeutics and Molecular Medicine, University of Nottingham)
Dr Anthony Holmes (NC3Rs)
M Baker, C Billington, LAC Chapman, IL Chernyavsky, H Croisier, LS Gallimore, IP Hall, JE Hiorns, AM Holmes, OE Jensen, SR Johnson, JM Phillips, CP Please, AF Smith, TJ Snowden

Problem Description

Asthma remains an area of considerable unmet medical need despite the availability of medicines that are effective for large numbers of patients; no cures exist and available therapies may be ineffective in some patients with moderate/severe forms of the disease. It is estimated that 300 million people currently suffer from the disease globally, and that by 2025 this figure will be closer to 400 million. Poorly predictive animal models of the human condition have contributed to the paucity of new treatments and there is a pressing need for the development of more predictive modelling approaches.

The role of airway smooth muscle (ASM) in asthma is extremely important since it is widely recognised as the key determinant of airway narrowing in the disease, and as an emerging effector of airway inflammation and remodelling, contributing to airway hyperresponsiveness.

The Study Group participants are asked to consider the following in the context of understanding the role of ASM cells in the asthma. To what extent do cell proliferation and apoptosis participate in the turnover rates of human ASM cells in normal and diseased tissue; including the nature of apoptotic and survival characteristics of the ASM, and the signals that the ASM receives under pathophysiological conditions?

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Study Group Report

In this work, we focus on the following two goals: formulating a model for the proliferation of ASM cells in vivo, and investigating how the greater reduction in lung function observed in people with asthma can be explained by an increase in ASM mass.

Initially, we assume that all ASM cells are proliferative and proliferate exponentially. This is shown to be unrealistic as it would lead to airway closure in a very small amount of time. Taking into account the presence of non-proliferative ASM cells as well as the ability for proliferative cells to become non-proliferative, it is found that bounded growth can occur.

In addition, a more realistic logistic growth model was considered. With this model, it was found that transition from non-proliferative to proliferative must be introduced in order to obtain monotonic growth.

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Follow-Up Activities

The following follow-up meetings have occured to continue work on aspects of this problem:

2012 ASM Growth in Asthma Follow-up Meeting
Wednesday 18th to Thursday 19th January 2012, University of Nottingham