Research focus:

Pulmonary injury:

Research in the PIIRL is focused on the resolution of inflammation and repair following lung injury, which leads to acute respiratory distress syndrome (ARDS), characterized by profound inflammation, edema, and tissue injury often resulting from trauma or severe pulmonary infection. Although ARDS survival rates have improved in recent years, 25 to 40% of cases remain fatal, and of those patients that do survive, persistent inflammation and fibrosis can result in continued pulmonary complications.

Current projects include assessing the role of metalloproteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), in regulating three different aspects of recovery following lung injury:

1) microvascular endothelial cell dysfunction;

2) macrophage polarization and apoptosis;

3) initiation and resolution of fibrosis.

Additional projects include examining the role of caspases and cell death in microvascular endothelial cell dysfunction during septic lung injury, as well as determining the effects of aging and exercise on the pathophysiology of lung injury. For these studies, we use multiple murine models of direct lung injury, including bleomycin (a model often used to study chronic lung injury and fibrosis) and Pseudomonas aeruginosa infection, as well as cecal ligation and perforation, a murine model of sepsis that results in indirect lung injury. Techniques such as flow cytometry, immunohistochemistry, quantitative real-time polymerase chain reaction, western blotting, and enzyme activity assays, in combination with culture of isolated primary cells, are then used to examine how specific cell populations are affected during lung injury.

Sulfactant:

Our research focuses on the pulmonary surfactant system, a film of lipids and proteins located at the inner surface of the lung. At this location, surfactant performs a function crucial for healthy respiration namely the reduction of surface tension at the alveolar surface. The importance function is best illustrated by the lung dysfunction that occurs in premature babies born with a deficiency in surfactant. Up until the 1980s, surfactant deficiency due to prematurity was one of the main causes of infant death. The development of exogenous surfactant to supplement the lungs of affected babies has dramatically improved infant survival in the western world. Over the last 25 years or so, our lab has investigated many different aspects of the pulmonary surfactant system. Currently, our focus is on three aspects:

1) Does vaping affect surfactant function and does that impact the development of lung injury?

The last decade has seen a dramatic increase in the use of electronic cigarettes (e-cig, or vaping) especially in adolescents. While initially hailed as a smoking cessation tool and a safe alternative to smoking, it is now clear that this habit is not without risks; case studies, epidemiological investigations, and laboratory findings have all indicated that vaping has negative consequences. How e-cigarettes cause acute lung damage is not understood. What we do know is that when e-cigarette aerosol is inhaled it gets into contact with a variety of cells and extracellular components. One of the first and critical substances encountered when aerosol reaches the small airways and alveoli is pulmonary surfactant. As such, our research investigates the effect of e-cigarette aerosols on surfactant.

Our governing hypothesis for this project is that exposure to e-cigarette aerosol will impact the pulmonary surfactant system, thereby making the lung more susceptible to acute secondary insults

Funding: Applied for & Lawson Health Research Institute

Collaborators: Dr Yi Zuo, Dr Sean Gill, Dr Jibran Khokhar, Dr Matt Cecchini, Dr Karen Bosma

People actually doing the work: Emma Graham, Sabrine Gehani, Anne Cao

2) Can exogenous surfactant be utilized to help the delivery of pulmonary therapeutic to the deeper regions of the lung?

Exogenous surfactant, as used for premature infants, has an ability to spread throughout the lung and open collapsed airways and alveoli. This ability of exogenous surfactant has inspired the idea that this material can be utilized as a delivery vehicle for pulmonary therapeutics. However, for exogenous surfactant to act as a carrier for pulmonary therapeutics, it needs to be designed to maintain functionality of both the delivered drug and the surfactant. Our lab is developing preparation to deliver either antimicrobial agents or anti-inflammatory agents to the lung using a variety of in vitro and in vivo approaches.

Funding: OTS, LHRI

People currently doing the work: Anne Cao.

Publications:

Banaschewski BJH, Veldhuizen EJA, Keating E, Haagsman HP, Zuo YY, Yamashita CM, and Veldhuizen RAW (2015) Antimicrobial and Biophysical Properties of Surfactant Supplemented with an Antimicrobial Peptide for Treatment of Bacterial Pneumonia. Antimicrobial Agents and Chemotherapy 59:3075-3083. doi: 10.1128/AAC.04937-14

Banaschewski BJH, Baer B, Arsenault C, Jazey T, Veldhuizen EJA, Delport J, Gooyers T, Lewis JF, Haagsman HP, Veldhuizen RAW, and Yamashita C. (2017) The Antibacterial and Anti-inflammatory Activity of Chicken Cathelicidin-2 combined with Exogenous Surfactant for the Treatment of Cystic Fibrosis-Associated Pathogens. Sci Rep. 14;7:15545. doi: 10.1038/s41598-017-15558-4.

Baer B, Veldhuizen EJA, Possmayer F, Yamashita C, and Veldhuizen RAW. (2018) The Wet Bridge Transfer System: A Novel Tool to Assess Exogenous Surfactant as a Vehicle for Intrapulmonary Drug Delivery. Discovery Medicine 26, 207-218.

Baer B, Veldhuizen EJA, Molchanova N, Jekhmane S, Weingarth M, Jenssen H, Lin JS, Barron AE, Yamashita C, and Veldhuizen RAW. (2020) Optimizing Exogenous Surfactant as a Pulmonary Delivery Vehicle for Chicken Cathelicidin-2. Sci Rep 10;10(1):9392. doi: 10.1038/s41598-020-66448-1.

Baer B, McCaig L, Yamashita Y, and Veldhuizen RAW. (2020) Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo. Lung 98:909-916 doi: 10.1007/s00408-020-00399-2.

Baer BJ, Souza LMP, Pimentel AS, and Veldhuizen RAW (2019) New insights into exogenous surfactant as a carrier of pulmonary therapeutics. Biochemical Pharmacology 164:64-73

3) How does age, sex, and exercise impact the response to mechanical ventilation.

Collaboration with Dr Sean Gill’s laboratory

Acute Respiratory Distress Syndrome (ARDS) is a condition of severe lung dysfunction associated with overwhelming inflammation and surfactant dysfunction. ARDS occurs predominantly in the elderly and has a mortality rate of approximately 40%. Its causes include sepsis, COVID-19 infection, trauma, pneumonia, and/or numerous other initiating events. Regardless of the cause, the main supportive therapy for ARDS is mechanical ventilation which, unfortunately, can initiate or propagate lung injury. It is therefore important to understand the effect of mechanical ventilation on the aging lung.

In addition to age, other factors can influence the outcomes in ARDS. For example, it is known that outcomes differ between males and females. Furthermore, our lab has previously shown that exercise may reduce the pulmonary inflammatory response due to sepsis. There is limited information on the effect of sex and exercise on the effects of mechanical ventilation.

At the cellular level, one of the key cells influencing the response to mechanical ventilation is the alveolar macrophage. These cells protect the alveoli and can transition into various functional states based environmental cues. In addition, these alveolar macrophages can, potentially, be targeted for therapy. Prior to such therapeutic approaches, we need to further understand the role of alveolar macrophages during mechanical ventilation, specifically the impact of age, sex and exercise.

The central hypothesis being tested in this project is that aging impairs, and exercise improves, alveolar macrophage function during VILI in males and females.

Funding: CIHR, LHRI, Western University

People currently doing the work: Aminmohamed Manji (Gill-lab), Cindy Pape (Gill Lab), Alexandra Troitskaya, Lynda McCaig

Publications:

Tyml K, Swarbreck S, Pape C, Koropatnick J, Feng Q, Veldhuizen RAW, and Gill SE. (2017) Voluntary running exercise protects against sepsis-induced early inflammatory and pro-coagulant responses in aged mice. Crit Care. 21(1):210. doi: 10.1186/s13054-017-1783-1.

Veldhuizen RAW, McCaig LA, Pape C and Gill SE. (2019) The effects of aging and exercise on lung mechanics, surfactant and alveolar macrophages. Exp Lung Res 45;113-122. doi: 10.1080/01902148.2019.1605633

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