Role of airway smooth muscle in asthma: Possible relation to the neuroendocrine system
Authors: Stephens Newman L. , Jiang He , Halayko Andrew 
Published: February 2005

AbstractThough not yet firmly established, it appears likely that the neuroendocrine system (NES) regulates airway smooth muscle function. As it is the latter which is altered in asthma, the importance of the role of the NES in this disease is clear. The fact that trnasmitters from the NE cells are released from their basal aspect, and are in close proximity to the subjacent airway smooth muscle, further indicates an interaction. The question then arises as to what are the experimental desiderata for conducting studies of the ASM. These should constitute what Sergei Sorokin has called the “Koch's postulates of airway smooth muscle research.”As human tissues from asthmatics are difficult to obtain, animal models have been developed. The requirements are that, in these animals, the allergy be IgE based, that a congenital or familial factor be operative, that a noncholinergic nonadrenergic inhibitory system be a component of the neural regulatory system, and that the antigen for immunization be of a type commonly found in human asthmatics. Ideally, evidence of clinical asthma and exercise‐induced asthma and nocturnal attacks should also be present. Unfortunately, no ideal animal models exist and one cannot talk about asthmatic animals, but only of animals with allergic bronchospasm.If in vitro research is to be conducted, there are additional requirements. The tissue should be from a relevant location. The tracheal smooth muscle which has been the favorite, purely because of its convenience, is not a good model. For the early asthmatic attack, central bronchi (3–5 mm diameter) should be used. Muscle strips obtained from them should be parallelfibred and the cartilage plaques should be carefully dissected away, otherwise they contribute unwanted frictional forces when velocity is measured. Care should be taken to ensure that the epithelial cell layer is intact, as evidence indicates that it may regulate airway muscle function, though this has not been establihsed for all the animal species used in asthma research.The isolated muscle strip should be in a steady state, particularly with respect to the functional variable under study, before definitive data are collected. Most importantly, it is shortening capacity that must be studied, as this is the in vitro analogue to in vivo narrowing of airways. Isometric force development provides information about wall stiffness and is of very little relevance to the elucidation of the mechanism of bronchospasm. Furthermore, as force is measured at the plateau of the record, it only yields data relating to latch bridges which seem to play little role in narrowing the airway. Unfortunately, isometric force is the most common measurement made, purely because it is easy to carry out, while shortening is technically more difficult.The above notwithstanding, if force is the parameter being studied, its correct normalization is a very important consideration. To make comparisons, force should be converted to stress. In tissues which are more than 5 mm in length and 5 mg in weight, the required cross‐sectional area can be obtained from the weight of the blotted tissue and its optimal length. For tissues smaller than this measurement errors render the approach invalid and direct measurements must be made using high performance optics. It must be remembered too that the cross‐sectional area of the tissue is only appropriate when the entire tissue consists of muscle, as for example, in the case of striated muscle. In smooth muscle, muscle content may only be 25%. For this reason, tissue stress should be converted to muscle cell stress and ultimately to myosin stress, as it is the myosin crossbridges that generate the force. Estimation of muscle stress requires quantitative morphometry while myosin stress requires morphometry of immunohistochemical micrographs.Finally, in conducting studies of shortening and velocity, the nature of the loading has to be kept in mind. Such studies are usually carried out with isotonic loads as this holds that variable constant. However, in vivo the load is more likely to be elastic or visco‐elastic, hence, in vitro studies should employ similar loading. In our own studies we have attempted to pay attention to the desiderata mentioned above. In bronchial smooth muscle (central airways) from 4‐month‐old, ragweed pollen‐sensitized dogs, we have found that maximum shortening capacity and velocity are both increased while force production is normal. These changes are typical of early disease. In addition, we have found that the compliance of the muscle's so‐called internal resistor is increased with sensitization. This could account for the increased shortening capacity of the muscle. We have also shown that the maximum velocity of the sensitized muscle is associated with increased myofibrillar ATPase activity. This results, not from a change in distribution in myosin heavy chain isozymes, but from increased phosphorylation of the 20,000 dalton myosin light chain that is due to an increased content of myosin light chain kinase. Our studies indicate that this increase is due to increased gene translation rather than transcription, as the content of messenger RNA for myosin light chain kinase is unchanged. © 1993 Wiley‐Liss, Inc.