Respirology

DISEASES OF THE AIRWAYS

Brief Description

This program is focussed on airways diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. The research has a range from mechanisms of disease to treatment and is conducted in clinical, laboratory, and epidemiological settings. Areas of research include genetics, mechanisms of airway inflammation and lung infection, treatment regimens such as delivery of genetic materials to the airways, drug trials for asthma and COPD, surgical lung volume reduction for emphysema, and respiratory rehabilitation. The program is integrated with the program in lung transplantation for emphysema and cystic fibrosis, where evaluation of the results is part of the research. The program also has a focus on early detection of exacerbations of airway disease, particularly asthma and COPD, as well as the effects of the environment, including industrial asthma. Gender issues related to asthma and COPD are included in the program. Specialized facilities include measurements of chemical mediators in the expiratory air and environmental exposure chambers.

Principal Investigators

Recent Original Research Publications

Ferreira IM, Harazi MS, Gutierrez C, Zamel N, Chapman, KR. Exhaled nitric oxide and hydrogen peroxide in patients with chronic obstructive pulmonary disease: effects of inhaled beclomethasone. Am J Respir Crit Care Med 164:1012-1015, 2001.

Brooks D, Krip B, Mangovski-Alzamora S, Goldstein RS. The effect of post-rehabilitation programs among individuals with COPD.  Eur Respir J 20:1-10, 2002.

Tarlo SM, Liss GM, Yeung KS. Changes in rates and severity of compensation claims for asthma due to diisocyanates: a possible effect of medical surveillance measures. Occup Environ Med 59:58-62, 2002.

Brook R, Brook J, Urch B, Vincent R, Rajagopalan S, Silverman F. Inhalation of fine particulate air pollution and ozone causes acute arterial vasoconstriction in healthy adults. Circulation 105:1534-1536, 2002.

Silkoff PE, McClean P, Spino M, Erlich L, Slutsky AS, Zamel, N. Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest 119:1322-1328, 2001.

Future Directions

The future directions of the program are to expand its scope to include increased interaction with basic scientists. Contacts have been made in several areas of molecular and cell biology that may have relevance to airways disease, and there are several scientists who are interested in joining the program, from the adult and pediatric areas. The ultimate goal will be to develop a strong interaction among scientists at all levels related to diseases of the airways, both pediatric and adult, ranging from bench to bedside.

SLEEP AND CONTROL OF BREATHING

Director	Contact
T. Douglas Bradley	University Health Network Toronto General Hospital NU 9-112 200 Elizabeth Street Toronto, ON M5G 2C4

Brief Description

The primary objectives of this research program are to determine: 1) mechanisms responsible for the development of obstructive (OSA) and central sleep apnea (CSA), and their neurological, behavioural and cardiovascular consequences, 2) the prevalences and risk factors for these disorders in specific populations, and 3) the efficacy of new therapies for these disorders. To these ends, a broad spectrum of research approaches, methodologies and collaborative-interdisciplinary investigation has been developed involving basic physiology, respirology, cardiology, nephrology-hypertension, physiatry, population health, and clinical trials. Sophisticated freely behaving animal preparations have been developed to investigate mechanisms of sleep-related pharyngeal collapse in OSA, to examine potential new therapies, and to study the cardiovascular consequences of OSA. Mechanisms responsible for OSA and CSA, and for their cardiovascular consequences are being investigated in humans with hypertension, heart failure and renal failure. Epidemiological studies are determining the prevalence, risk factors for, and consequences of sleep apnea in populations with hypertension, heart failure, renal failure and cerebrovascular disease. Finally, investigator initiated randomized trials are determining the effects of treating OSA and CSA with CPAP on blood pressure in patients with refractory hypertension, and on mortality in patients with heart failure.

Principal Investigators

Name	Department	Major Research Interest
Douglas Bradley	Medicine	Sleep apnea pathophysiology, epidemiology
John Floras	Medicine	Autonomic physiology, heart failure
Vlasta Hajek	Medicine	Epidemiology of stroke
Patrick Hanly	Nursing	Sleep in ICU; sleep apnea in renal failure
Victor Hoffstein	Medicine	Epidemiology of sleep apnea
Richard Horner	Medicine	Brainstem mechanisms of sleep, upper airway
Alexander Logan	Medicine	Sleep apnea and refractory hypertension
John Parker	Medicine	Sleep apnea in heart failure
Eliot Phillipson	Medicine	Animal models of sleep apnea

Recent Original Research Publications

Parker JD, Brooks D, Kozar LF, Render-Teixeira CL, Horner RL, Bradley TD, Phillipson EA. Acute and chronic effects of airway obstruction on left ventricular performance. Am J Respir Crit Care Med 160:1888-1896, 1999.

Sin D, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 160:1101-1106, 1999.

Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes Respiration. Circulation 102:61-66, 2000.

Horner RL, Rivera MP, Kozar LF, Phillipson EA. The ventilatory response to arousal from sleep is not fully explained by differences in PaCO₂ between sleep and wakefulness. Journal of Physiology, 534:881-890, 2001.

Hanly P, Pierratos A. Improvement of sleep apnea in chronic renal failure treated by nocturnal hemodialysis. N Engl J Med 344:102-107, 2001.

Future Directions

The future goals are to achieve greater scientific productivity and international impact in sleep-related breathing disorders. We envisage strengthening of the program in several key areas. Cellular and molecular techniques need to be introduced to examine mechanisms of chemoreception, the influence of sleep-wake state on respiratory control, and the adverse effects of hypoxia. Research in upper airway anatomy and physiology in humans needs to be strengthened to translate discoveries from more reduced preparations into potential therapies. Expansion of the human cardiovascular aspect of our program is essential to explore mechanisms responsible for the cardiovascular complications of sleep apnea. Finally, the epidemiological aspect of the program needs to be enhanced to permit examination of the public health and economic implications of diagnosing and treating sleep apnea.

LUNG INFLAMMATION AND ACUTE LUNG INJURY

Director	Contact
Gregory Downey	Medical Sciences Building Room 6264 1 King's College Circle Toronto, ON M5S 1A8

Brief Description

The primary objectives of this research program are to determine: 1) molecular and cellular mechanisms of inflammatory tissue and lung injury in the setting of sepsis and shock; 2) the mechanisms of ventilator-induced lung injury and strategies to minimize injury in the setting of ARDS; 3) the optimal definition, prevalence and risk factors for these disorders in critically ill patient populations; 4) the long term outcomes from ARDS and critical illness; 4) the discovery and efficacy of new therapies for these disorders. To these ends, the group has developed diverse research approaches, methodologies, and collaborative-interdisciplinary investigations involving the physiology, clinical respirology, critical care, population health, and clinical trials communities. Sophisticated murine transgenic and murine embryonic stem cell technologies have been developed to study leukocyte function. The mechanisms responsible for ventilator-induced lung injury are being investigated in animal models of lung injury and sepsis, and in humans with critical illness and ARDS. Epidemiological studies are focused on determining the optimum definitions, prevalence, risk factors for, and long term consequences of ARDS.   Clinical studies are underway to study the effectiveness of novel modes of mechanical ventilation such as high frequency oscillation.

Principal Investigators

Name	Department	Major Research Interest
Chung-Wai Chow	Medicine	Inflammatory lung injury
Gregory Downey	Medicine	Inflammatory lung injury
Niall Fergusson	Medicine	ARDS definition and epidemiology
John Granton	Nursing	Acute lung injury/ARDS
Laura Hawyraluk	Medicine	Ethics and critical illness
Patrick Hanly	Medicine	Sleep disturbance in the ICU
Margaret Herridge	Medicine	Outcomes from critical illness
Brian Kavanagh	Pediatrics	Acute lung injury
Neil Lazar	Medicine	Ethics and end of life care
Stephen Lapinsky	Medicine	Technology in Critical Care
Mingyao Liu	Surgery	Epithelial function in lung injury
John Marshall	Surgery	Leukocyte apoptosis in sepsis
Sangeeta Mehta	Medicine	Mechanical ventilation
Hugh O’Brodovich	Pediatrics	Regulation of epithelial ion transport
Martin Post	Pediatrics	Epithelial cell function
Ori Rotstein	Surgery	Redox signaling in sepsis
Bill Sibbald	Medicine	Microvascular dysfunction in sepis
Arthur Slutsky	Medicine	Ventilator-Induced Lung Injury
Tom Stewart	Medicine	Mechanical ventilation
Keith Tanswell	Pediatrics	Oxidant mediated lung injury
Michael Ward	Medicine	Hypoxic regulation of vascular tone
Haibo Zhang	Anaesthesia	Lung injury, mechanical ventilation

Recent Original Research Publications

Zhang H, Downey GP, Suter PM, Slutsky AS, Ranieri VM. Conventional mechanical ventilation is associated with bronchoalveolar lavage-induced activation of polymorphonuclear leukocytes: a possible mechanism to explain the systemic consequences of ventilator-induced lung injury in patients with ARDS. Anaesthesiology 97:1426-1433, 2002.

Teoh H, Zacour M, Gunaratnam L, Ward ME. Increased myosin light chain phosphatase expression impairs aortic smooth muscle activation after hypoxia. Am J Physiol (Heart Circ Physiol) 284:H1182-H1189, 2003

Mehta S, MacDonald R, Hallett DC, Lapinsky SE, Aubin M, Stewart TE. Acute oxygenation response to inhaled nitric oxide when combined with high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med 31:383-9, 2003.

Kruger JM, Fukushima T, Cherepanov V, Borregaard N, Loeve C, Shek C, Sharma K, Tanswell AK, Chow CW, Downey GP. Protein tyrosine phosphatase MEG2 is expressed by human neutrophils: localization to the phagosome and activation by polyphosphoinositides. J Biol Chem 277:2620-2628, 2002.

Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, Cooper AB, Guest CB, Mazer CD, Mehta S, Stewart TE, Barr A, Cook D, Slutsky AS, for the Canadian Critical Care Trials Group. One-year outcomes in survivors of the acute respiratory distress syndrome. New Eng J Med 348:683-693, 2003.

Future Directions

The future goals are to sustain this high level of scientific productivity and achieve greater international impact in the fields of innate immunity, lung injury, and sepsis. We envisage strengthening of the program in several key areas. Cellular and molecular techniques will be developed to examine mechanisms of leukocyte regulation in the context of the innate immune system, inflammation, sepsis, and acute lung injury. We will expand our interactions with the genomics and microarray facilities in Toronto to examine mechanisms of lung injury and sepsis and the genetic predisposition to critical illness. We have recently recruited several young clinical investigators with expertise in clinical epidemiology and outcomes research who will examine the public health and economic implications of ARDS and critical illness.