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Ultrastructural basis of airway smooth muscle contraction Kuo, Kuo-Hsing

Abstract

Smooth muscle is ubiquitous and controls vital function in our body. Airway smooth muscle (ASM) is the main effecter that controls the caliber and hence airflow resistance of the airways. Dysfunction of the ASM is a major contributor to the distress of asthma and other obstructive airway diseases. The emphasis of my thesis research is to elucidate the basic mechanism of ASM contraction, especially from the ultrastructural point of view. The general hypothesis, based on previous observations on mechanical behavior of the tissue, is that ASM cells are highly adaptable to their external environment and are able to maintain optimal contractile function over a large length range. Specific hypotheses regarding mechanisms of length adaptation of ASM are 1) the myosin filaments are structurally labile in the relaxed state, and it is this lability that facilitates plastic remodeling of the ASM to accommodate large changes in cell geometry while maintaining optimal contractile function; 2) in ASM cells adapted to long lengths, polymerization produces more myosin filaments to account for the observed increase in muscle power output and shortening velocity; the reverse is true for ASM adapted to short lengths. Three major groups of experiments were carried out in this thesis research. The first group of experiments was carried out to examine inter- and intra-cellular organization of the contractile filaments. We showed electronmicroscopic and functional evidence that contractile filaments in ASM lied parallel to the longitudinal axis of the cell bundle, in contrast to the obliquely arranged filaments depicted in conventional models. The parallel arrangement of the contractile filaments was observed to be maintained despite the fact that individual cells were spindle-shaped. This was accomplished through filament attachment to dense plaques on the cell membrane and the plaques were in turn connected to like-structures on neighbouring cells. Intracellularly the parallel arrangement was maintained despite the centrally located nucleus. This was accomplished by attachment of actin filaments to the nuclear envelope and making the nucleus a force transmitting structure. The results suggest that ASM cells form a mechanical syncytium and are able to function properly only as a group. The second group of experiments was carried out to examine myosin filament lability and its relationship to the ability of the muscle to generate force. Specifically we studied the relationship between isometric force generation and myosin thick filament density in cell cross-sections, measured electronmicroscopically, following length oscillations applied to the relaxed porcine trachealis muscle. The results indicate that thick filaments in ASM are labile; depolymerization of the myosin filaments can be induced by mechanical strain, and repolymerization of the thick filaments underlies force recovery after the oscillation. The third and final group of experiments examined the mechanisms by which plastic adaptation of ASM to large changes in muscle length is accomplished. In these experiments we showed that isometric force produced by ASM was independent of muscle length over a 2-fold length change; cell cross-sectional area was inversely proportional to cell length, implying that the cell volume was conserved at different lengths; shortening velocity, power output and myosin filament density varied similarly to length change. The data can be explained by a model where additional contractile units containing myosin filaments are formed and placed in series with existing contractile units when the muscle is adapted at a longer length. In summary, results from this thesis research has provided much needed ultrastructural data for constructing a preliminary model that explains some aspects of plastic behavior of ASM. The most important finding of this research is perhaps that the ultrastructure of smooth muscle is not as "permanent" as that of striated muscle; the malleable contractile apparatus of smooth muscle makes it necessary to interpret the ultrastructural data in the context of functional states under which the tissue is fixed for examination.

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