CRITICAL ILLNESS RESEARCH

                                                                                                                                   

                                                                                                                                   

                     

Dr. Jim Lewis                                                                                        Dr. Ruud Veldhuizen (info below Dr. Lewis)
 

Dr. Jim Lewis, M.D.,                                                                                                         Dr. Ruud Veldhuizen
 
 
Dr. Jim F. Lewis, MD
Clinician/Scientist - Lawson Health Research Institute, St Joseph's Health Centre
Professor, Respirology Division, Department of Medicine, Physiology & Pharmacology, University of Western Ontario
Assistant Dean – Clinical Research, University of Western Ontario

PULMONARY SURFACTANT/ LUNG INJURY

General Research Interests  - Evaluate the role of surfactant alterations and/or surfactant administration in acute lung injury
                                             - Determine the role of surfactant in pulmonary and/or systemic inflammation
 

Background    Pulmonary surfactant functions to lower the surface tension within the alveoli thereby maintaining alveolar stability.  Alterations of the surfactant system have been shown to contribute to the pathophysiology of the lung injury associated with the Acute Respiratory Distress Syndrome (ARDS).  My research is focused on characterizing surfactant alterations in animal models of lung injury and patients with ARDS.  These studies have shown that surfactant alterations contribute to the lung dysfunction associated with ARDS.  We have also evaluated the mechanisms responsible for these alterations with the aim of preventing progressive lung dysfunction.
 We have utilized several different animal models of acute lung injury including systemic sepsis induced by cecal ligation and perforation, subcutaneous N-nitros-N-methylurethane (NNMU), acid aspiration, and repetitive saline lavage and lung transplantation.  Surfactant alterations have been characterized and the mechanical response for these changes have been probed.  Several different species including sheep, dogs, rabbits, rats and mice have been utilized for these models.  We have also investigated various treatment strategies involving exogenous surfactant administration in these models in patients with ARDS.  We are currently involved in a multicentre clinical trial evaluating the efficacy of a recombinant exogenous surfactant preparation in patients with severe ARDS.  Future studies are aimed at determining the role of surfactant in host defense and the role of surfactant alterations in ventilation induced lung injury (VILI).

Specific Research Projects
• Characterizing alveolar surfactant metabolism in systemic sepsis-induced lung injury
• Characterizing surfactant alterations in an animal model of pseudomonas pneumonia
• Determining the effects of mechanical ventilation on the endogenous surfactant system and the mechanisms responsible    for these changes
• Evaluating the role of high frequency oscillation (HFO) in acute lung injury
• Evaluating the role of surfactant alterations in the ischemia-reperfusion injury associated with lung transplantation in dogs
• Evaluating the functional significance of alveolar surfactant aggregate changes in vivo
• Evaluating aerosolization of surfactant through an endotracheal catheter device
• Determining the effects of surfactant alterations on systemic organ dysfunction utilizing a combination of an ex vivo lung model, a perfused lung model and in vivo animal models of lung injury.
• Evaluating regional differences in lung compliance utilizing computerized tomography imaging
• Evaluating the role of exogenous surfactant administration in patients with ARDS
• Evaluating the role of aerosolized exogenous surfactant in patients with acute asthma

 For a complete list of my publication please see PubMed
 

Dr Ruud A.W. Veldhuizen  Ph.D. (Med)
Principal Investigator, Lawson Health Research Institute
Associate Professor in the Dept. of  Physiology & Pharmacology
The University of Western Ontario
Room G454, Lawson Research Institute
St. Joseph's Health Centre
268 Grosvenor St.
London, Ontario    N6A 4V2
Canada
Phone: (519) 646-6100 x6288
Fax: (519) 646-6110
e-mail: rveldhui@uwo.ca

Research Interest

INTRODUCTION:
The main focus of research in my laboratory is the effect of mechanical ventilation of the lung on the pulmonary surfactant system and on inflammatory cytokines. Mechanical ventilation is a essential supportive therapy for patients with acute lung injury. However, in recent years it has become apparent that mechanical ventilation can also damage the lung. This had let to the predicament of requiring the use of a potentially harmful intervention in patients with acute lung injury. The objective of my research is to elucidate some of the processes involved in the development and/or propagation of lung injury due to mechanical ventilation. By understanding how lung injury occurs we may be able to develop therapies aimed at preventing this complication. Two of the factors that are thought to be involved in mediating the harmful effects of mechanical ventilation are alterations of the pulmonary surfactant system and increases in inflammatory mediators within the lung.
>
           Schematic representation of the overall hypothesis of our research.  Mechanical ventilation affects cytokines
             and surfactant, which also influence each other.  This contributes to lung dysfunction and systemic
             inflammation.
 

EXPERIMENTAL APPROACHES: In general, the studies in the lab consist of an initial animal experiments which include a physiological assessment of lung function followed by extensive biochemical, histological and molecular biological analyses of the lung. Specifically we utilize rat and mouse models of ventilation induced lung injury to examine the effects of mechanical ventilation  on pulmonary surfactant and inflammatory cytokines.
The rat model allows us to characterize  a large number of ventilation strategies and is being utilized in conjunction with other injury models. For example, we are examining the susceptibility of septic lungs to ventilation induced lung injury. The rat model is also utilized to examine therapies that can mitigate ventilation induced lung injury (such as exogenous surfactant therapy).
The mouse model of ventilation induced lung injury is utilized for a more thorough examination of the mechanisms involved in this type of injury. We use transgenic animals that are either deficient or overexpress specific proteins of interest such as Tumor Necrosis Factor   and Surfactant associated protein A.

COLLABORATIVE STUDIES: There are a variety of collaborative research projects ongoing in the lab. The topics of these studies are; pulmonary surfactant subtype conversion, effects of surfactant on lymphocyte proliferation, alterations of pulmonary surfactant in patients with the acute respiratory distress syndrome, the use of surfactant supplementation for the treatment of Acute Respiratory Distress Syndrome, pulmonary surfactant in lung transplantation and the relationship between endogenous nitric oxide production and the pulmonary surfactant system. Collaborators on these studies are Drs Lewis, Possmayer, Fraher, Metha and McCormack.

For more information visit  The Lung Lab at:  http://www.lhrionhealth.ca/LHRI/research/centre_critical_illness/lung/

For a complete list of my publications please see PubMed

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