Molecular Mechanics & Asthma

May has been designated Asthma Awareness Month by NHLBI and the Asthma and Allergy Foundation of America. The World Health Organization estimates that 235 million people worldwide suffer from asthma. The Biophysical Society is taking this opportunity to highlight how advances in basic research contribute to our understanding of this disease. BPS member Anne-Marie Lauzon of the Meakins-Christie Laboratories of the Research Institute of the McGill University Health Center studies the role of specific proteins in determining the contractile properties of smooth muscle, in particular as they pertain to the problem of airway hyperresponsiveness in asthma.

Figure Lauzon-Asthma

What is the connection between your research and asthma?

Asthma is an inflammatory disease characterized by airway hyperresponsiveness, an exaggerated bronchoconstrictive response to various stimuli. Because airway smooth muscle (ASM) is the final effector of bronchoconstriction, it is commonly believed to be hypercontractile in asthma. This paradigm is supported by animal models but has never been demonstrated in human airways. We measure the biophysical properties of asthmatic and control human ASM to determine whether or not it is hypercontractile in asthma. We study the ASM bundle mechanics as well as their molecular mechanics in order to elucidate what is abnormal with asthmatic ASM. Molecular mechanics measurements allow us to investigate the mechanisms of ASM contraction and also provide us with additional tools to measure the mechanics of ASM in airways too small to be dissected and studied at the bundle level.

Why is your research important to those concerned about asthma?

Even though asthma was first described in the 1860s there is still no cure. Current medications alleviate and control the symptoms but there is still no therapy, no doubt because of our lack of understanding of the exact causes and mechanisms responsible for asthma.  Millions of Americans suffer from asthma and environmental factors worsen those numbers every year.  In addition to the poor life quality of asthmatic subjects, in some cases asthma can be fatal.

To date, most research on asthma has focused on the inflammatory aspect. Few laboratories address the ASM mechanics in asthma and even fewer address it directly in human samples. Along with my collaborators at the Meakins-Christie Laboratories of the Research Institute of the McGill University Health Center, we address the effect of inflammation on ASM mechanics from the whole human subject to the intracellular molecular motor level. This multi-scale approach allows us to verify at given scale levels theories developed at other levels.

How did you get into this area of research and how long have you been working on it?

As an undergraduate student doing a double major in Physics and Physiology at McGill University, I got very interested in the rheology of air and blood flow. Montreal counts several world renowned laboratories that perform pulmonary research so I had the chance of getting involved quite early on in pulmonary mechanics studies. Then, I pursued at McGill University a Ph.D. addressing the time course of bronchoconstriction, followed by a post-doctoral training at the University of California, San Diego, where I studied the distribution of pulmonary ventilation in weightlessness. A second post-doctoral training at the University of Vermont allowed me to specialize in the molecular mechanics of contractile proteins.  In July 1998, I was recruited back to the Meakins-Christie Laboratories to start my research on the mechanics of human ASM in asthma.

Do you receive public funding for this work? If so, from what agency?

My research is currently funded by the Canadian Institute of Health Research, the Réseau en Santé Respiratoire du Québec, and the Natural Science and Engineering Research Council of Canada (funding for the basic aspect of smooth muscle contraction). I was also recently part of a multi-PI research group funded by the National Institutes of Health (NIH).

Have you had any surprise findings thus far?

The biggest surprise that we have had so far in this research is that even though asthmatic ASM is commonly believed to be hypercontractile, it is not at all easy to demonstrate its altered mechanical properties. We started our investigations with the trachealis muscle because of its ease of dissection and we found that it behaves exactly the same in asthmatics and in controls. Because we previously showed in rat models of asthma that inflammatory cells can enhance ASM mechanics, and because more inflammatory cells are found in the peripheral airways than in the trachea, we concluded that the trachealis muscle was probably not representative of peripheral ASM mechanics. This later fact was verified in a horse model of asthma, the horse with heaves, in which we showed a perfectly normal trachealis in horses with hypercontractile peripheral ASM. Repeating these studies with human peripheral airways is however not a simple task, but it is the main endeavor of my current post-doctoral fellows Gijs Ijpma and Oleg Matusovsky and research assistants Nedjma Zitouni and Linda Kachmar.

What is particularly interesting about the work from the perspective of other researchers?

Our thorough characterization of the mechanical properties of asthmatic ASM will delineate the relative importance of other mechanisms also potentially responsible for airway hyperresponsiveness and asthma. Such other mechanisms include alterations in airway-parenchyma inter-dependence, neural control, surfactant properties, etc.

What is particularly interesting about the work from the perspective of the public?

Getting a better understanding of asthma will take us one step closer to potentially curing it, but at a minimum, of finding better relief medications.

Do you have a cool image you want to share with the blog post related to this research?

See the figure at the beginning of this post. Airway tree section from a control (A) and an asthmatic (B) subjects in which the actin is stained with TRIT-C phalloidin thus, showing primarily the airway smooth muscle. Airway cross-section of a control horse (C) and a horse with heaves (D), a disease very similar to human asthma. (E) A dissected smooth muscle strip hooked up in an organ bath for mechanics measurements.

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