Looking to the stable for a new asthma model

Is asthma reversible? Believe it or not, but the answer may be coming to you straight from the horse's mouth! AllerGen NCE Inc. and the CIHR Institute for Infection and Immunity are funding partners on a novel research programme led by clinician-scientist Dr. Jean-Pierre Lavoie of the Université de Montréal, Faculty of Veterinary Medicine, involving asthmatic horses. This research team aims to find out whether lung remodeling in asthma is a reversible condition.

Most asthma research involving animal models is undertaken using mice and rats, which have a short lifespan relative to humans and do not develop the disease naturally in their environment. Lavoie notes that asthma sufferers and horses with heaves share similar disease characteristics, including airway remodeling, increased muscle mass, increased granulocytes and a TH2 cytokine bias. This unique study will look at airway smooth muscle remodeling in the lung tissue of 12 horses (six symptomatic and six asymptomatic controls) over a one-year period using a repeated process of whole lung biopsy.

AllerGen trainee Mathilde Leclére administers Fluticasone.

Periodic minimally invasive thoracoscopic surgery will be used to remove lung tissue samples from the horses during asthma exacerbation and again following a course of treatment with Fluticasone, a drug produced by GlaxoSmithKline. This will enable the research team to undertake laser microdissection of lung tissue samples before, during and after Fluticasone treatment to assess whether airway remodeling has occurred and correlates with clinical improvement of asthmatic horses.

In addition to Principal Investigator Lavoie, whose veterinary practice is centred at Saint-Hyacinthe, Quebec, the multi-disciplinary research team includes Dr. James Martin, McGill University, who specializes in animal models for asthma; Dr. Jacques Lussier, a molecular biologist, Faculty of Veterinary Medicine, and research assistant Josiane Lefebvre-Lavoie.

The project is also providing outstanding research, surgical and sample management including biobanking experience to Network trainees Mathilde Leclère (Doctor of Veterinary Medicine and PhD candidate); Anouk Lavoie Lamoureux (PhD candidate); Trohadio Munoz (MSc candidate), Laureline Lecoq (DES large animal equine internal medicine resident); Marie-Laure Cortes (Intern, Equine Medicine and Surgery); and Kantuta Moran (undergraduate student).

Lavoie notes that the remodeling caused by asthma also occurs in the periphery of the lung. Normally researchers study the central airways because they are readily accessible, however, this project will allow researchers to gain valuable insights into the long-term changes in lung function in the airway smooth muscle mass of the smaller airways at the lung periphery. Laser microdissection of the smooth muscle tissue is expected to yield significant new insights into lung tissue remodeling.

AllerGen investigator Dr. Jean-Pierre Lavoie with a thoracoscopic surgery post-operative research subject.

For the study of the temporal variation in tissue remodeling, a team of veterinary surgeons from the Université de Montréal led by Dr. Marcel Marcoux, has developed a novel surgical technique for obtaining lung periphery tissue samples under thoracoscopic guidance. This new surgical technique is supported by industrial partner Tyco, which is seeking to extend the use of its surgical tools from abdominal surgery to lung surgery in humans. An investigation of the role and changes in peripheral blood and lung neutrophils in the horses under study is being supported by an NSERC grant. The role of neutrophils in horses parallels the role and action of eosinophils in humans.

In addition, gene expression will be studied using Subtractive Suppressive Hybridization, microarray technologies and real time PCR. The wild card in the team's research program is the genetic analysis being undertaken. Lavoie notes "This line of inquiry could lead to truly novel discoveries, the implications of which we can examine in collaboration with AllerGen researchers from the Gene-Environment Interactions programme."

Lavoie credits AllerGen and the CIHR Institute of Infection and Immunity for supporting his novel, multidisciplinary approach to the use of animal models to inform the treatment of asthma in humans within this groundbreaking research programme.

The team has also benefited from AllerGen's network structure. It has leveraged the expertise of iCapture technicians at the University of British Columbia to provide advice about optimizing the results of the team's use of laser microdissection technology in its analysis of the banked lung tissue samples.