Human airway smooth muscle promotion of mast cell survival and proliferation, and altered state of activation in asthma
thesisposted on 2009-11-09, 11:39 authored by Fay Marie Hollins
Asthma is a condition that is characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), chronic airway inflammation and airway remodeling. There is microlocalisation of mast cells within the airway smooth muscle (ASM) bundle in asthma at a level significantly above health and other respiratory diseases. These cells are recruited and their survival promoted. However, their functional consequences have yet to be discovered. AHR in asthma is a result of increased responsiveness of the ASM to agonist and has found to increase with localized mast cell numbers. This phenomenon could be a result of an intrinsic abnormality or of local effects. So far, it has yet to be elucidated. We sort to examine this phenomenon of the presence of mast cells within the ASM and the increased responsiveness of the ASM; mechanisms involved in sustaining mast cell numbers, and the intrinsic differences of ASM between asthma and health. ASM had the ability to maintain survival and promote proliferation of co-cultured mast cells, a mechanism supported by the actions of stem cell factor (SCF), interleukin (IL)-6 and cell adhesion molecule (CADM)-1. There was a physical interaction in mast cell adhesion to ASM between CADM1 and the SCF receptor. The co-culture also enhanced constitutive mast cell degranulation. Intracellular calcium levels of ASM from asthmatic patients at rest were found to oscillate to a great degree. Following stimulation with agonist, the ASM gave a reduced intracellular calcium response. However, their contractile ability measured still remained greater than ASM isolated from non-asthmatic subjects. SCF, IL-6 and CADM1 supported the survival of mast cells co-cultured with ASM. Although ASM from asthmatic subjects produce a reduced intracellular calcium response to agonist, at baseline these cells are more activated and they still retain their increased contractile response. Mechanisms which may contribute to the altered airway physiology in asthma.
Supervisor(s)Brightling, C.; Bradding, P.
Date of award2009-07-03
Awarding institutionUniversity of Leicester