The basic science at FIRH is focussed on animal models of lung disease (asthma, COPD and fibrosis), small animal imaging using PET and SPECT/CT, smooth muscle biology, and bone marrow progenitors in lung inflammation and repair. FIRH has developed facilities such as the Sputum Research Laboratory and the Aerosol Research Laboratory. FIRH also hosts the coordinating center for the Canadian Healthy Infant Longitudinal Development Study (CHILD) birth cohort study. FIRH is a site for many different clinical trials in asthma, COPD and lung fibrosis.

Notable achievements by FIRH scientists in the respiratory field include:

• FIRH methodologies have become the international standard in the development of indirect methods to study airway inflammation by non-invasive techniques.
• Firestone scientists developed the most widely used methods of bronchial provocations using inhaled histamine, methacholine and allergens.
• The Aerochamber™ valved holding chamber for MDI aerosols, used internationally to improve delivery of inhaled medication, was developed by FIRH faculty.
• Firestone scientists (in 1989) developed the first Canadian guidelines for the treatment of asthma; these subsequently had a significant impact on the development of international guidelines.
• FIRH scientists fostered and coordinated the development of the national birth-cohort collaboration leading to the CIHR-funded Canadian Healthy Infant Longitudinal Development (CHILD) study, whose central administration is at FIRH.

• The scope of research conducted at FIRH includes molecular, cellular, whole animal, patient and population studies.
• FIRH has been successful in translational research, particularly in airway diseases and pulmonary fibrosis
• Weekly back-to-back clinical and research rounds, which include presentations from local, national and international speakers, are well attended and very interactive.
• The research faculty at FIRH are intensely collaborative within St. Joseph’s Hospital, McMaster University, nationally and internationally.
• FIRH has considerable success in competing for peer-reviewed funding, and in collaboration with industry.
• FIRH continues to publish highly influential research papers in excellent peer reviewed journals.
• FIRH faculty are recognized by membership in National and International committees and in frequent presitigious speaking/consulting invitations.

In some areas, FIRH researchers perform or lead investigations that are unique in Canada, examples are:

• Coordinating center for the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study.
• AllerGen Clinical Investigator Collaborative.
• Sputum Research and Clinical Laboratory.
• Aerosol Research Laboratory.
• Small animal imaging using PET and SPECT/CT.
• Studies of bone marrow progenitors in lung inflammation and repair.
• Electrophysiological studies of airway smooth muscle combining mechanical, electrical, and biochemical measures.
• Airway peptide challenges.
• Chronic allergen inhalation and airway remodelling in mice.
• Preclinical models of lung injury and repair.
• Center for biomarkers and clinical trials in pulmonary fibrosis.

MR Sears, N Johnston, M Quinn

The wealth of information on asthma emerging from the relatively small (n=1000) New Zealand multidisciplinary longitudinal birth cohort study the respiratory arm of which Dr Sears has led for 3 decades, the recent increase in prevalence of asthma, and the availability of new tools and techniques for examining infant lung function, innate and acquired immunity, infections, endocrine and stress-related factors, together with the advances in genetic analyses, were the stimuli for planning a new larger birth cohort study in Canada to provide new information on risk factors, genetic, host and environmental, leading to asthma and influencing its progression. This Canadian Healthy Infant Longitudinal Development Study of at least 5,000 children and families is now funded by CIHR jointly with AllerGen NCE, and is being implemented in 2008, with maternal recruitment during pregnancy in 4 centres across Canada. Over 40 scientists from multiple disciplines are collaborating in this national birth cohort study, which is also supported by federal health- and environment-related partners.  Central coordination and administration is the responsibility of Dr Sears supported by a study executive and a scientific advisory board including international birth cohort leaders.

FIRH initiated development of a data library of all hospitalisation and ER encounters for respiratory disease in Canada from 1995 onwards.  Statistical analyses of spatial and temporal patterns of respiratory disease in these databases identified potent seasonal variations in asthma exacerbations and between age and sex groups.  Prospective studies of these patterns led to identification of the factors driving them and clinical trials of therapeutic interventions to reduce the impact of seasonal asthma epidemics

P Nair, MR Sears, PM O’Byrne

Scientists in FIRH have been responsible for many landmark studies in asthma management, from early trials of inhaled steroids to more recent studies of leukotriene antagonists, long-acting β-agonists, combination therapies, and monoclonal antibodies.  Results of clinical trials have contributed significantly to evidence-based guidelines for asthma management. The ability to combine clinical indices such as quality-of-life measures with physiological assessment of airway resistance and responsiveness, and evidence of airway inflammation has allowed the group to achieve a high international reputation and the financial support of the pharmaceutical industry.  Research has ranged from small proof of concept studies to large single-center and multi-centre studies as appropriate to the clinical question being asked.

A particularly unique feature of the research programme has been the application of inflammometry to routine clinical practice. Quantitative cell counts in induced or spontaneous sputum have helped to identify phenotypes of bronchitis associated with airway diseases. This has led to a major research programme to investigate the role of individualized anti-inflammatory therapy based on the type of bronchitis and to develop novel therapies for eosinophilic and neutrophilic bronchitis and for infective and non-infective exacerbations associated with specific cell types. Measurements of inflammation is being utilized to understand the presence and type of bronchitis associated with a number of triggers of exacerbations such as stress, air pollution, gastric acid reflux, and infections. More recently, the utility of other measurements such as pH and temperature of exhaled breath condensate, urinary metabonomics, and responsiveness to inhaled mannitol are being investigated.

PM O’Byrne in collaboration with G Gauvreau, L-P Boulet, JM Fitzgerald, DW Cockcroft

Allergen bronchoprovocation tests have been used for more than five decades in the investigation of respiratory allergic diseases such as asthma and rhinitis. These bronchial challenges are now well standardized and can offer key-information on the therapeutic potential of new agents and on their anti-inflammatory effects on the airways. Both standard and low dose allergen provocations are safe when performed by experienced investigators and do not lead to persistent worsening of asthma or change in airway function. The evaluation of new therapeutic agents by these methods can also provide important information on the mechanisms of development and persistence of airway diseases.   Many of the methods used for these standardized challenges, as well as for the evaluation of allergen-induced airway inflammation have been developed at FIRH.  The AllerGen Network of Centers of Excellence Clinical Investigator Collaborative (CIC) was developed by Drs. PM O’Byrne and L-P Boulet to exploit the competence in these methodologies to study the possible efficacy of new molecules for the treatment of asthma.  The CIC includes investigators originally trained at FIRH.

New information regarding the cellular mechanisms involved in asthma has led to a long list of potential treatment measures, and the ready availability of a large pool of well-characterized patients places the group in a unique leadership position to evaluate these novel approaches.  Studies which have been completed by the AllerGen CIC, since its inception in 2004, have included the evaluation of a disaccharide, thought to be the anti-inflammatory component of inhaled heparin, an ultra-long acting inhaled β2-agonist, inhaled anti-sense against the common β-chain of IL-3, IL-5 and GM-CSF and the chemokine receptor CCR-3, and monoclonal antibodies directed against IL-9 and IL-13.  Current studies are evaluating a monoclonal antibody directed against C5a, and a new formulation of a monoclonal antibody against IgE.  These studies have, in addition, helped further understand the role and significance of some putative pro-inflammatory mediators in allergic asthma.

G Cox, J Miller, L Janssen

Since joining the faculty in the early 1990’s Dr’s Miller and Cox have collaborated on a number of studies including the first randomized trial of video assisted thoracoscopy vs. open lung biopsy for the investigation of interstitial lung disease, the role of lung volume reduction surgery for emphysema and the potential for early detection of lung cancer using sputum-based test of altered mucopolysaccharides. 

Following on the successful examination of the role of lung volume reduction surgery for emphysema our centre has participated in trials of endoscopic treatment for emphysema involving the placement of valves that allow decompression of areas of hyperinflation. 

In recent years Drs Miller and Cox have developed bronchial thermoplasty and translated the application of this technology from the pre-clinical arena to clinical trials for treatment of asthma.  The close collaboration of an expert thoracic surgeon with clinicians capable of describing and treating asthma accurately has been key to the successful implementation of this new technology.

More recently the collaboration between the surgical and clinical sections of the Firestone has focused on the implementation of endo-bronchial ultrasound (EBUS) to guide transbronchial biopsy of adjacent lymph nodes and masses.  This service is scheduled for implementation in summer 2008 and will provide clinical, educational and research opportunities.

In addition, studies have begun to explore the biological and biochemical changes brought on by bronchial thermoplasty.  There is intriguing evidence that this may involve a temperature-sensitive ion channel (of the “transient receptor potential” family).   Finally, a novel application of the bronchial thermoplasty technique is being evaluated in the arena of cardiovascular disease.  Coronary artery by-pass grafting (CABG) surgery is the most effective method for restoring myocardial perfusion in patients with multi-vessel coronary artery disease.  However, a common complication is post-surgical vasospasm, often leading to complete occlusion of the graft, with considerable morbidity and even mortality.  We have begun to explore the possibility of thermally treating the arterial grafts in order to reduce their muscle mass: preliminary in vivo studies in rats and rabbits, as well as in vitro studies using human radial arteries, are highly encouraging that this novel approach may alleviate this complication.

M Inman, L Janssen, , PM O’Byrne, M Stampfli

The concept of airway hyperresponsiveness (AHR), its quantification with histamine and methacholine challenge, and its clinical relevance were all established in the early years of the clinic. The measurement of AHR remains an important component of asthma assessment where it is used both diagnostically and as a marker of disease severity and need for treatment.

The association between AHR and asthma is the basis for several research directions at FIRH, focusing on determining the mechanisms underlying AHR. The ultimate aim of these approaches is to increase understanding to the point that new treatment strategies to either prevent, or reverse, this airway dysfunction can be developed. Currently this work is being performed in both basic animal models and clinical investigations.

Mouse models of brief or chronic exposure to allergen are allowing Dr Inman and collaborators to investigate the contribution from both inflammatory and structural events to AHR. Using both experimental (ovalbumin) and natural (house dust mite and ragweed) allergens, this group has described a variable component of AHR that fluctuates with the level of airway inflammation as well as a sustained component that appears to be related to “remodelling” changes in the airway wall. The major tools available to this laboratory are state of the art airway function systems as well as morphometric methods to assess for structural changes in the airway wall. Interventional studies aimed at investigating underlying mechanisms are possible using drugs, antibodies, adenoviral delivery of genes as well as genetically modified transgenic or gene deficient animals. These models are the basis of an ongoing CIHR grant held by Dr Inman, as well as numerous annual peer review grants from the Canadian Thoracic Society. An additional CIHR grant based on this model and investigating the role of GABA is held by Dr Wei-Yang Liu from U of T, with Dr Inman as a Co-Applicant. Currently, with peer reviewed funding we are investigating the impact of allergens and inflammation on epithelial permeability and how this impacts on AHR.

The potential therapeutic relevance of these models is illustrated by the interest from the pharmaceutical industry. Currently, collaborations with industry are allowing us to investigate the roles of eosinophils (GSK and in collaboration with Dr Jamie Lee), corticosteroids (AstraZeneca), IL-9 (Medimmune), IL-4receptor (Amgen) and IL-33 (Amgen).

Several clinical investigations in the laboratories of Dr O’Byrne, Dr Hargreave and collaborators are investigating the effects of directing therapy against specific targets, including cells (primarily the eosinophil) or mediators (including leukotrines and specific cytokines) on AHR in asthmatics.

Asthma is associated with marked accumulation of isoprostanes, products of peroxidative attack of membrane lipids.  Our group has shown that these autacoids can evoke bronchoconstriction and induce AHR. We are now exploring the cellular and signalling mechanisms underlying isoprostane-induced AHR.  The data suggest that RhoA-kinase is important in this phenomenon, although there are also important changes in Ca2+-handling.

 R Sehmi, MD Inman, P Nair, PM O’Byrne

Evidence for the activation of hemopoeitic events within the bone marrow and indications of the lung-homing of these cells during an inflammatory response has spawned a novel area of research into modulation of hemopoietic stem cell trafficking in asthma. Using both human and mouse models of asthma the factors that regulate the egress of hemopoietic stem cells to the lungs and the ultimate fate of these cells within the lungs are being addressed. In addition, therapeutic agents that modulate the migration of these cells or their terminal differentiation are being investigated to understand the exact role of hemopoietic stem cells in the development of airway pathology in asthma. The strength of this area of research is the ample supply of human bone marrow samples from Dr. O’Byrne’s clinical research subjects and the availability of animal models of allergen-induced airway hyperresponsiveness from Dr. Inman’s group. There is a growing interest in the contribution of hemopoietic stem cells to the remodeling changes induced by chronic inflammation within the asthmatic airways elements of which are currently being investigated, including neoangiogenesis and lung homing of fibrocytes and smooth muscle progenitor cells.

In collaboration with Dr. Nair, similar studies are also being carried out in patients with COPD in whom the profile of hemopoietic stem cell traffic to the lungs diverges from that reported for asthmatics. The role of hemopoietic stem cells in immunosurveillance through Toll-like receptors (TLRs) is being investigated specifically in relation to early onset of atopy. Cord blood derived hemopoietic progenitor cells from children at either high or low risk of developing atopy are being assessed for functional expression of TLRs. This work is being performed in collaboration with Dr. Judah Denburg.    

These novel findings will be succeeded by therapeutic intervention and further work in human subjects and the sensitized-mouse model to identify the molecular mechanisms that stimulate migration of progenitor cells into lung tissue following allergen challenge.

M Larché, PM O’Byrne, MD Inman, P Nair, M Stampfli

The role of the immune system and, in particular, allergic responses in the pathogenesis of asthma is well established. Recent studies with anti-IgE monoclonal antibodies have demonstrated that even severe asthma has a significant dependence on IgE. A major focus of research at the FIRH is the immunobiology of asthma. In vivo studies of provoked asthma and therapeutic intervention in both human and animal models are employed to address specific hypotheses. The strength of this research program is the integration between clinical and experimental models. Asthma is provoked in the clinical laboratory by inhalation of whole allergen (and shortly by synthetic T cell epitopes) leading to airway narrowing that can be studied under carefully controlled conditions. Baseline and post-challenge samples of blood, bone marrow, sputum, bronchoalveolar lavage and mucosal bronchial biopsies allow investigation of the modulation of the immune response during active disease. Interventional studies with both established and novel experimental compounds, provides an unique opportunity to study the role of individual pathways and molecules in pathogenesis.

Dr. Larché has a particular interest in the role of T cells in asthma and has developed novel clinical and experimental models to address the hypothesis that allergen-specific T cells are able to induce airway narrowing independently of mast cells/basophils. Challenge of allergic asthmatic subjects either intradermally or by inhalation with allergen-derived T cell epitopes results in the induction of isolated late asthmatic responses (LAR). The ability to study the immunopathology of the LAR in isolation has provided an unique insight into the disease. Furthermore, Dr. Larché and colleagues have also demonstrated the ability to induce profound immunological tolerance following delivery of small doses of short allergen-derived synthetic peptides to asthmatic subjects. Tolerance was associated with reductions in skin, nose and lung sensitivity to allergen challenge, improved quality of life, suppression of pro-inflammatory Th1 and Th2 responses to allergen and the generation of functional, IL-10-secreting, allergen-specific, regulatory T cells. In addition to in vivo experiments in human subjects, Larché has developed experimental models that recapitulate the clinical models. Low dose peptide-based immunotherapy in mice with allergic airways disease provides an opportunity to study immunological mechanisms that are inaccessible in human subjects. The ability to study immune responses in the target organ in the mouse by removal of lung and other tissues (spleen, lymph node etc) will inform future clinical studies and provide definitive mechanistic data. Together with Dr. Inman, Dr. Larché is developing a murine model of peptide-induced isolated LAR and a number of allergen-specific models of peptide immunotherapy.

Dr. Larché also has other active areas of research at McMaster University and the FIRH outside the area of respiratory disease. These include collaborations with the Division of Rheumatology on the role of citrullination of target antigens in rheumatoid arthritis and on the role of autoimmune responses to MHC molecules in the pathogenesis of Systemic Sclerosis (with Drs. MJ Larché, D. Haaland, N Khalidi and E Kaminska). Mechanisms of allograft rejection and models of antigen-specific tolerance induction in transplantation form a collaborative study with Drs. P Margetts and D Russell in the Division of Nephrology.

LJ Janssen, P Nair, G Cox, M Kolb

FIRH faculty are leaders in the field of airway smooth muscle electrophysiology, having been the first to characterize membrane currents evoked by a variety of agonists (the classical neurotransmitter acetylcholine, the inflammatory mediator histamine and the neuropeptide substance P), to describe the basic features of the major depolarizing ion current (Ca2+-dependent chloride), to examine directly the non-selective cation current involved in refilling of the intracellular Ca2+ pool, and to propose a novel role for reverse-mode sodium-calcium exchange in refilling of that pool.  Also, these scientists provided the first description of the “superficial buffer barrier” function of the sarcoplasmic reticulum in airway smooth muscle, a model which accounts for many paradoxical features of Ca2+-handling and excitation-contraction coupling in ASM; this model allows for a complete uncoupling of membrane-associated events (e.g., activities of ion channels and many enzymes) and those occurring in the deep cytosol (i.e., the contractile apparatus).  Attention is now being directed at the roles of RhoA and RhoA-kinase in excitation-contraction coupling. 

Another new area has been the identification of the ability of human airway smooth muscle cells to migrate towards chemotactic signals. This is a proposed mechanism for the accumulation of smooth muscle cells in the submucosa of patients with long-standing asthma. Current research explores the regulation and clinical relevance of this phenomenon, particularly the effect of cellular inflammation, cytokines and chemokines and neuroendocrine influences including nuclear hormone receptor ligands and leptin.

This research group has also long been interested in the effects of free radicals and reactive oxygen species on airway smooth muscle.  Those studies resulted in an interest into the biology of isoprostanes: a novel group of molecules generated by peroxidation of membrane lipids.  The studies have not only shown that isoprostanes can mimic the direct effects of free radicals (and, thus, may mediate those effects), and to evoke powerful biological responses from virtually every cell type in the lung (airway smooth muscle, pulmonary and bronchial vasculature, epithelium, cholinergic innervation and pulmonary lymphatics, while others have shown effects on inflammatory cells and vascular endothelium), but have more recently shown that they can also reproduce many of the key features of asthma, acute lung injury and pulmonary hypertension.

Finally, we have also investigated the interactions between the airway wall and the surrounding parenchyma, both in an elastolytic murine model of emphysema as well as in vitro treatment of lung slices with proteolytic enzymes (collagenase, elastase).  Using this approach, our researchers have quantified the effects of altered extracellular matrix proteins on the dynamics of airway constriction, and have more recently found evidence for an intramural force/structure which opposes airway collapse, one not involving parenchymal attachments, transmural pressure gradients or surfactant-mediated reduction in surface tension.

A McIvor, N Johnston, M Quinn

Using computer based serial monitoring technologies Neil Johnston and Andrew McIvor have initiated studies of the factors that produce predictable epidemic peaks of COPD exacerbations. Epidemic peaks during the Christmas period and those associated with periods of influenza and RSV infection contain the majority of severe COPD exacerbations requiring emergent treatment.  An inception cohort of COPD patients was assembled during 2006 and expanded during 2007. A team of support staff has been assembled to monitor daily data submission and perform home assessments during exacerbations.  Serial monitoring of COPD patients during these high risk periods has identified factors that drive exacerbations and opportunities for future intervention studies to reduce the risks associated with them. Currently our model, SOPs and technology is being considered as the foundation for a multicenter study to examine the determinants of exacerbations and the use of early detection to initiate new therapies.

In addition, Dr. McIvor is conducting a CIHR funded population survey of asthma and obesity, and studies of quality management and health outcomes in COPD to assess current diagnosis and management of  asthma and COPD in primary care and ongoing efficacy and effectiveness trials assessing new therapies for COPD, such as  PDE4 inhibitors and neutrophil elastase inhibitors.

DC Todd, P Nair

The development of the Collaborative Respiratory Care Program (CRCP) and the revival of the Respiratory Rehabilitation Program have provided the clinical framework from which to develop a research program that will evaluate systemic inflammation in COPD, utility of outcome measurements, and novel therapies in COPD (including non-pharmacologic interventions such as neuromuscular electrical stimulation).  In addition, the program will facilitate the development and evaluation of methods to stream patients with COPD into programs that will best suit their needs including inpatient versus outpatient respiratory rehabilitation, palliative care programs, geriatric assessment programs, etc.

An observational study evaluating a multi-compartmental model of COPD in patients when stable and during an exacerbation led by Dr. D. Todd and Dr. P. Nair has received start-up funding.  This study will serve as a model for future interventional studies evaluating the effect of pharmacologic and non-pharmacologic therapies on systemic inflammation in COPD.  Other pilot studies evaluating inflammation are underway including PET imaging to detect lung inflammation by measuring the uptake of  18FDG in COPD patients (in collaboration with M Dolovich).

In addition, a new instrument to assess motivation for respiratory rehabilitation is being developed for assessment during the evaluation process of patients with COPD.  Finally, studies that will evaluate determinants of success (including systemic/airway inflammation) during respiratory rehabilitation are being planned.

The FIRH is uniquely positioned to study pulmonary inflammation in COPD using measurements (i.e. sputum cell counts) already widely used in asthma and other diseases of airway inflammation.  Also, PET imaging is being used in a pilot study to detect lung inflammation by measuring the uptake of  18FDG in COPD patients.

M Kolb, G Cox, M Inman, R Labiris, L Janssen, M. Stampfli

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, which is unresponsive to treatment and associated with high mortality rates. IPF is characterized by persistent and progressive accumulation of mesenchymal cells, fibroblasts and myofibroblasts, and extracellular matrix (ECM) in the lung parenchyma along with tissue distortion, leading to respiratory failure. Current thinking indicates the pathogenesis of IPF is associated with chronic inflammation and aberrant wound healing, mediated by cytokines such as TNFa and TGFb. However, recent evidence developed by Drs. Kolb and Gauldie, and studies of others, indicate that progression of fibrosis may proceed independent of inflammation and pathogenesis may involve aberrant direct interaction between injured epithelial cells and mesenchymal cells, with associated inflammation being an epi-phenomenon. One of the mainstays of the research done by Drs Kolb and Gauldie is gene transfer and genetic manipulation to assess susceptibility and development of pulmonary fibrosis in rodents. Their broadly recognized data imply that processes defining progressive or resolving fibrogenesis differ in molecular events downstream of the TGFb mediated tissue response to injury and repair. They have shown that interaction between cells of the epithelium and mesenchyme through TGFb, the TGFb Receptor and the Smad signaling pathway, are integral to the initiation and persistence of fibrosis in the lung.

One of the key hypotheses of Drs Kolb and Gauldie is that inflammation is involved in fibrogenesis at the initiation stages, likely mediated through TGFb, but inflammation may not be necessary at the persistence stage. Together, they hold a CIHR grant to examine the regulation of signals and mediators, downstream of TGFb, along with mediators that counteract the activity of TGFb, in regulating the persistence of fibrosis. They also found the presence of a circulating cell, the fibrocyte, in patients with fibrosing disorders and currently determine the role of this cell in the persistence of fibrosis, using both data from human patients and animal disease models. Further, Dr Kolb has developed an ex vivo organ culture, that allows him to examine the effect of the altered microenvironment and aberrant matrix in activation of TGFb through integrin-matrix interaction as a contributor to the persistence of fibrosis. It is likely that similar mechanisms, from a molecular and cell biology perspective, are involved in airway remodelling, which will be studied with Dr M Inman.

In addition to molecular probes and lung pathology, Dr Kolb currently applies modern imaging tools such as SPECT, PET, CT and MRI for assessment of drug efficacy in animal models of lung fibrosis, in collaboration with Dr R Labiris. Similarly, Dr Kolb has, together with Dr M Inman, established lung physiology assessment in live animals and measurement of pulmonary hemodynamics as outcome for drug studies in rodents. The challenging hypothesis is that a combined “clinic-pathological-radiological score” in animals may be a superior outcome for drug efficacy studies in animal, similar to the previously proposed “CPR-score” for human disease.

Dr Janssen has begun to apply confocal fluorimetric microscopy to study Ca2+-handling in cultured human pulmonary fibroblasts, finding a variety of agonists (purines such as ATP, acetylcholine, thrombin, caffeine) to evoke dramatic Ca2+-waves, particularly in the nuclear regions of these cells.  We are now exploring the possibility that gene transcription (e.g., of extracellular matrix proteins, or of cytokines) by fibroblasts is triggered/regulated by the frequency of these Ca2+-waves.

M Kolb, G Cox

The past 5 years has seen a number of clinical trials on IPF, driven by ATS, ERS and NIH together with a substantial interest from pharmaceutical companies. However, there is still no efficient therapy identified and further trials are needed. Previous efforts from large companies have focused on Toronto as primary Ontario site for these trials. The recruitment of Dr Kolb has allowed the FIRH to expand the ILD clinic which is run by Drs Cox and Kolb and now provides medical care for patients with ILD. This together with the strong international recognition of the basic research in lung fibrosis done at McMaster and the Firestone Institute has propelled the awareness that our center is indeed an ideal site for clinical trials. Dr Cox and Kolb are Principal Investigator on two actively recruiting trials, and a third trial being currently reviewed and likely installed in summer 2008. In addition to drug trials, Drs Kolb and Cox have an exciting project on the usefulness of circulating fibroblast progenitors as biomarkers of disease activity in IPF and scleroderma-associated ILD, the latter in collaboration with Dr N Khalidi as a part of the Canadian scleroderma registry that has several hundred patients involved.

MB Dolovich, NR Labiris, G Cox, P Nair

Two major research scanners for imaging human subjects are housed in the Imaging Research Center (IRC) at St Joseph’s Hospital: a Siemans Biograph16 PET/CT scanner and a GE 3T magnet. The PET/CT machine was recently installed and has been in limited operation for approximately 12 months. The setup for using aerosols of 18F-fluorodeoxyglucose (18F-FDG) was established at McMaster (and now in the IRC), allowing PET investigations of 3D aerosol deposition/distribution in the lung under a variety of conditions. Studies such as 1) the influence of airways obstruction on the distribution of PET 18F-FDG aerosols of different particle sizes has been assessed in healthy volunteers and subjects with cystic fibrosis (M Dolovich); 2) whether lung inflammation in the CF lung could be detected by the (PET) measurement of FDG uptake (Labiris, Dolovich); 3) changes in the 3D distribution of ventilation in asthmatic subjects using inhaled PET aerosol tracers following airway caliber changes resulting from direct challenge to the airways of bronchoconstrictor and bronchodilator agents (M Dolovich).  

Current PET and SPECT studies include deposition and kinetics of radio-labelled drugs (M Dolovich and R Labiris); changes in regional ventilation in asthmatic subjects following ICS therapies of different particle sizes (M Dolovich); and the investigation of lung inflammation in COPD patients with a range of disease severities using 18F-fluorodeoxyglucose uptake and correlating these outcomes with sputum cytology results (M Dolovich in collaboration with G Cox and R Labiris). A 3D shell model has been developed and is used to analyze the regional distribution of radioactivity/drug in the lung and to correlate these data with established geometric models of the lung.

Small animal imaging utilizing PET and SPECT/CT is available at McMaster. Dr Labiris is currently investigating temporal changes in lung density, inflammation and fibrogenesis in an animal model of pulmonary fibrosis (with Dr M Kolb). Other studies currently underway involve measurements of ventilation/perfusion changes in mice exposed to cigarette smoke (Dr M Stampfli) and the effects of acute bacterial infections on mucociliary clearance on cigarette smoke exposed mice (Dr M Stampfli).

Research studies using hyperpolarized helium and magnetic resonance imaging are in the planning stages (M Dolovich, M Noseworthy). Preliminary work has been initiated (coil design and testing, pulse sequences) in preparation for studies investigating changes in diffusion in asymptomatic compared to chronic smokers in collaboration with G Cox.  In addition, the possibility of using the SPECT clinical scanner located in the St Joseph’s Hospital Dept Nuclear Medicine for research investigating lung mucociliary clearance and epithelial permeability utilizing 99mTc tracers is being explored.  

The Firestone Research Aerosol Laboratory (M Dolovich, R Labiris) that has been established in FIRH is one of only seven facilities in North America and Europe that combines new (3D) imaging techniques with traditional physiological and pharmacological methods. The laboratory moved from McMaster to St Joseph’s in August ’07 and is now set-up and functioning.

There are several dimensions to the work of the Aerosol Laboratory: 1) in vitro characterization of medical aerosol formulations and drug delivery systems; 2) aerosol support for 2D and 3D imaging of lung deposition and distribution and pharmacokinetics of aerosolized radiolabelled formulations, including simulation of delivery under a variety of inhalation conditions; 3) in vitro measurements of epithelial cell cilia function (beat frequency, wave form, cilia length, shape) in relation to disease and pharmacologic interventions. Using high-speed digital imaging and computer processing, function and structure of nasal and bronchial cilia are currently being investigated in healthy volunteers and COPD patients with varying severity of disease (M Dolovich, G Cox). Outcomes will be correlated with sputum cell counts and conventional pulmonary function measurements. Other projects involve measuring the effect of hyperosmolar agents on ciliary beat frequency (M Dolovich). A grant has been submitted to determine the effect of exacerbations on the function and structure of epithelial cell cilia in COPD (M Dolovich, P Nair). In addition, cell culture using human bronchial and nasal epithelial primary cells is being established in the Aerosol Lab to provide model systems for disease and for the investigation of mechanisms as well as the effects of a variety of experimental therapeutic agents on cilia function. Plans are to establish methods for knockdown of specific proteins in situ which could lead to a better understanding of the molecular and cellular pathogenic mechanisms of COPD. 

CJ Allen, P Nair

Dr Allen has been studying the respiratory complications of gastroesophageal reflux since 1984.  In 1992 he began collaborating with Dr Mehran Anvari in the prospective study of patients with gastroesophageal reflux undergoing laparoscopic antireflux surgery. This patient population is one of the largest cohorts in the world and has successfully followed patients for up to 10 years.  An unusual feature of this cohort has been the large number of patients presenting with respiratory symptoms (predominantly cough) who have undergone antireflux surgery.  This successful research programme led to the award of 2 major grants in 2000. A grant from the Ontario Ministry of Health funded a prospective study of cough in the patients with gastroesophageal reflux taking part in a CIHR funded study.  To support this study a cough clinic was established.  Databases were set up to prospectively gather data (including atopic status, airway responsiveness to histamine, and induced sputum examination) on all the patients referred to the cough clinic including the patients who were eventually randomised to the CIHR study.  This study completed gathering data in 2007 and is currently undergoing analysis. 

Novel strategies are being developed and evaluated to understand the mechanisms of cough. These include monitoring of cough using videometry and portable digital sound recording devices and relating them to the type of bronchitis associated with cough. Acidity of breath measured in exhaled breath condensate is also being evaluated as a method of detecting gastro-esophageal reflux.