[Truncated abstract] The extent to which an airway narrows is strongly influenced by mechanical loads on airway smooth muscle (ASM). This thesis considers both dynamic and static mechanical loads. Dynamic load describes the time varying load on airways produced by oscillatory breathing movements. Static load is that present at a fixed lung volume ie. without breathing. In the intact lung static load principally comprises the pressure across the airway wall, that is transmural pressure (Ptm), and elastic after-load arising from distortion of airway and lung tissue by the narrowing airway. The experiments performed in this thesis were designed to answer several outstanding questions relating to how dynamic and static loads regulate airway narrowing. Dynamic load from breathing movements cyclically stretches ASM, which produces a number of physiological and cellular effects. For example in ASM strips a period of cyclical stretch reduces subsequent ASM contraction. However the response of the whole airway to dynamic load may differ from isolated ASM where non-muscle tissue also contributes. The first aim of this thesis was to characterise the response of the whole airway to dynamic load and determine whether the airway wall modifies the effects produced by ASM length cycling. Static after-loads restrict ASM shortening providing a limit to airway narrowing. Two primary sources of airway wall load include cartilage and the mucosal membrane which contribute to airway compliance. The relative importance of cartilage and mucosa to airway wall compliance and airway narrowing is unclear. ... Results demonstrate that airway narrowing is restricted by Ptm but not by parenchymal elastic after-load. The major findings of this thesis are: (1) dynamic loads produced by breathing movements regulate airway responsiveness through cyclical airway expansion and elongation; (2) the reported effects of cyclical stretch on ASM contraction differs in situ 8 possibly due to modification by one or more biomechanical or physiological properties of the airway wall; (3) parenchymal elastic after-loads, previously thought to be important during bronchoconstriction, do not restrict airway narrowing. Given the absence of an effect of parenchymal elastic after-load on airway narrowing, the static mechanical load on ASM therefore comprises Ptm and airway wall stiffness, with important contributions from cartilage and mucosa depending on lung volume.
|Doctor of Philosophy
|Unpublished - 2006