Investigation of aging-related pathways associated with an increased risk of emphysema in HIV-infected patients

Because antiretroviral therapy has enabled people to live longer, those with HIV now face a growing epidemic of age-related chronic diseases such as chronic obstructive pulmonary disease (COPD). The reason for this increased risk, however, remains unknown. Compelling evidence suggests that HIV infection triggers an inflammatory process which causes the premature aging of inflammatory and structural cells due to cell exhaustion from repeated divisions and oxidative stress. This concept of “inflamm-aging” (coined by Claudio Franceschi) applies fittingly to the development of COPD as well, where the primary trigger is cigarette smoke.

Given the dual pro-inflammatory states of HIV and COPD, Dr. Leung hypothesizes that the accelerated development of emphysema in HIV is driven in part by inflammation-induced cell aging related to the HIV infection and potentiated in the lungs by cigarette smoke. Dr. Leung's laboratory has found peripheral leukocyte telomere lengths, a marker of cell senescence, are shorter in HIV-infected patients who also have COPD compared to HIV-infected patients without COPD. Those with the most severe airflow obstruction on spirometry and those with the greatest extent of emphysema as visualized on CT scanning also appear to have the shortest telomere lengths. The laboratory group is now exploring whether similar relationships hold in lung cells obtained from HIV-infected patients.

Physical activity in individuals with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a lung condition that affects more than 75,000 British Columbians. People with COPD have a shortness of breath, chronic cough, and can experience difficulties with the activities of daily life, such as showering, walking, and social activities. Many people with COPD have regular flare-ups, or exacerbations, of their lung condition. These exacerbations result in a severe shortness of breath and overall weakness and fatigue and sometimes lead to long hospital stays. These flare-ups and long hospital stays can cause severe problems with activity tolerance, which then further increases the risk of future flare-ups.

The objective of Dr. Pat Camp's research program is to investigate how physical activity can improve the health outcomes of people who are hospitalized with a COPD flare-up. This research program will include a systematic literature review to summarize the current state of knowledge, validating tools to measure activity in hospitalized COPD patients, and determining if exercise programs for hospitalized patients can improve their quality of life and health outcomes. In addition, Dr. Camp's research program will include projects that incorporate patient input about what activities are important to them, which will indicate the level and type of activity that is necessary in order for these patients to be discharged safely from the hospital.

By developing a thorough understanding of how exercise leads to increased health in COPD patients, this research program aims to improve the quality of life and overall health of patients hospitalized with acute COPD flare-ups. Future work will extend these innovations to other chronic lung disease populations, such as patients with lung transplants or interstitial lung disease.

The role of the airway epithelium NLRP3 inflammasome in asthma pathogenesis

Asthma is a respiratory disease that afflicts more than two million Canadians. Asthmatics experience both airway inflammation and changes in the airway structure, called airway remodeling, when they inhale allergens, pollutants and other insults, and this leads to an exacerbation. The airway epithelium is the first site of contact for inhaled substances and has been shown to be different in asthmatics than in non-asthmatics. In specific cells of the body, including the airway epithelium, a danger sensor called the “inflammasome” can signal as part of the immune system to produce inflammation in response to an insult. Currently, we do not know if this airway epithelium danger sensor functions differently in asthmatics than in members of the general population and if this contributes to the development and progression of asthma.

Dr. Jeremy Hirota's hypothesis is that if the airway epithelium danger sensor is present, it increases airway inflammation and contributes to development and progression of asthma. His research goal is to determine the specific mechanisms responsible for airway epithelium danger sensor activation and to find out if it is more active in asthmatics. He is using three distinct approaches for his proposed research: 1) Using lungs that have been donated for medical research, he will compare the danger sensor between non-asthmatics and asthmatics. 2) Using the same donated lungs, he will grow human airway epithelial cells and expose them to an allergen or mechanical wound and then measure the resulting inflammation. 3) He will explore the role of the airway epithelium danger sensor during periods of allergen exposure by comparing normal mice to mice with a dysfunctional danger sensor.

The increasing prevalence of asthma in Canada demonstrates a requirement for a greater understanding of mechanisms leading to disease development and for new approaches to prevent or treat this disease. This research has the potential to highlight new therapeutic targets to control both excessive airway inflammation and the development of asthma.

Innate immunity and its influence on cardiovascular function

In Canada, severe infection, or sepsis, is the most common acute illness causing death. Patients with severe infections can go into shock as a result of progressive cardiac collapse and can die within 24 to 48 hours. The mortality rate of sepsis is 40%. The fact that this rate has not changed in the last 30 years illustrates that very little is known about how infection causes cardiovascular dysfunction and that very little is known about the best ways to prevent this from occurring.

Dr. John Boyd's research program is using a two-pronged approach to understand how sepsis causes progressive cardiac collapse. The objective of his clinical research program is to identify prognostic factors and to characterize the cardiac response to infection in patients with sepsis. Specifically, he is focusing on very early enrollment of acutely ill patients with infection presenting to the St. Paul's Hospital emergency department in order to identify prognostic factors such as new biomarkers and the presence of emerging infections. He will characterize their cardiovascular response to infection using a bedside cardiac ultrasound. Although previous work in this area has been done, patients were recruited from critical care units 24 to 36 hours following admission, too late to identify prognostic markers and intervene to improve outcome.

As a complementary approach, Dr. Boyd's pre-clinical (basic) research program is taking a molecular approach and using the immune system as a tool in the fight against cardiovascular collapse. He has identified a "counter-regulatory" receptor which appears able to reverse the heart damage induced by other receptors in the same family. The identification of this receptor will hopefully lead to the development of a targeted intervention for sepsis-related cardiovascular dysfunction. Dr. Boyd's clinical research program aims to answer simple but as-yet unstudied questions such as the optimal volume of IV fluid and how one can reliably diagnose infection. Although the results of his laboratory work are not yet close to reaching the bedside, they may potentially lead to therapies in the future.

Fostering cultural safety in nursing practice with people experiencing problematic substance use

The purpose of this project is to generate new knowledge that will foster understanding of what constitutes safe nursing care in acute care settings for people who are experiencing problematic substance use and social disadvantage. The target audience will be practicing nurses who provide care to people experiencing substance use, as well as health care administrators, nursing leaders and policy makers. The key research question is: What is culturally safe care from the perspective of patients and nurses in acute care settings and what supports the delivery of culturally safe care?

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The role of Apical Junction Complex in airway epithelial repair and differentiation in asthma

Asthma is a serious global health problem, affecting over 300 million people worldwide. The disease is predominantly an inflammatory disorder of the conducting airways, and can be treated or controlled using current therapies. However, un-controlled asthma leads to continual inflammation and damage, resulting in permanent scaring which is termed airway remodeling. Airway remodeling can be defined as changes in the composition, content and organization of cellular and molecular constituents of the conducting airways. One of the structural changes that occurs as a result of airway remodeling is detachment of the cells that line the surface of the airways, called the epithelium. In normal airways, the epithelium forms a barrier against the inhaled external environment which includes aero allergens, viruses and particulate matter, through the formation of apical junction complexes (AJCs). In asthma, part of the abnormal response to inhaled allergens is thought to be due to impaired barrier function caused by damage to the airway epithelium and loss of AJCs. Emerging evidence suggests that AJCs are able to influence other aspects of epithelial function such as release of inflammatory mediators and mechanisms of epithelial repair. Building on earlier work in this area, Dr. Tillie-Louise Hackett’s current research is designed to determine whether AJCs play an important role in normal airway epithelial repair and if the mechanisms involved are altered in asthmatic patients. The results of her research will provide scientists and clinicians with a better understanding of the pathological mechanisms that contribute to multiple respiratory diseases. In addition, Dr. Hackett’s findings will open avenues for the development of new therapeutics to improve the lung health of Canadians living with obstructive lung diseases, such as asthma and Chronic Obstructive Pulmonary Disorder.

Utilization of an Interactive Internet-based Platform for Managing Chronic Diseases at a Distance

Chronic diseases represent an increasing burden for both the patient and healthcare system. Many people also now have more than one chronic disease. For those people with chronic diseases living in rural areas, the risk for hospitalization is more than 60% greater. These patients and their primary care providers face an enormous challenge in meeting their day-today health needs that patients with chronic diseases have.

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Genetic Susceptibility to Inflammatory Airway Diseases

Chronic inflammatory airway diseases include asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Together, these conditions contribute to an enormous burden of death and disability worldwide. It’s estimated that 10 to 15% of 13- to 14-year-olds in Canada are asthmatic. COPD affects close to half a million Canadians 35 and older, currently ranking 12th worldwide as a cause of lost quantity and quality of life and projected to rank 5th by the year 2020. CF is the most common, fatal genetic disease affecting Canadian children and adolescents.

There is compelling evidence supporting a hereditary pattern to virtually all of the major inflammatory diseases. For example, more than 1,000 CF-causing gene mutations have been identified. Although some mutations are associated with less severe disease, patients possessing the same mutations often show great variation in disease severity and progression. Significant advances in molecular genetics make it possible to discover the specific genetic variants that determine individual susceptibility to these illnesses.

Dr. Andrew Sandford is investigating the genetic variants that cause susceptibility to asthma and COPD. He is also focused on the role of genetics in CF. He works with a unique group of patient families who have previously been involved in studies to establish the associations between their genetic variations and their disease symptoms. A better understanding of the causes of inflammatory airway diseases will contribute to better prevention and/or intervention measures and more efficient treatment strategies.

IL-13 and the Glycomics of Airway Epithelial Repair

Asthma is the most common chronic disease in childhood and continues to increase in prevalence in adults. Every day, lung airways are subjected to challenges that damage their lining, known as the epithelium. The accumulation of damaged epithelium is a common and consistent feature in those with asthma, suggesting that asthmatics are more susceptible to damage, or are less able to repair the epithelium, than people without asthma. While the epithelium normally protects the underlying tissue from noxious particles, epithelial damage may account for airway hyper-reactivity in asthma, and the chronic nature of the disease. Previously supported by an MSFHR Scholar award, Dr. Delbert Dorscheid is researching the role of glycosylated proteins – proteins that have a sugar or sugar chain added to them – in epithelial repair. These proteins appear on the surface of cells that mediate repair, and their formation heralds the start of cell repair. Dorscheid has identified a specific protein that’s linked to the beginning of this process. His goal is to observe any changes in the modification and regulation of this receptor in asthmatic airways and healthy airways, and determine how this may influence injury and repair of the airway. The overall objective is to better understand the differences in asthmatic airways to develop new treatment strategies to improve the quality of life of those who suffer from this disease.

Increased nitric oxide bioavailability through regulated eNOS-Caveolin-1 antagonism

Hypertension (high blood pressure) has a direct link to aging and is a major risk factor for atherosclerosis (narrowing and hardening of the arteries over time), stroke, heart attack and chronic renal failure. All known cardiovascular diseases, including hypertension, have in common a disease called endothelial dysfunction. The endothelium is a layer of cells that line the cavities of the heart, as well as the blood and lymph vessels. With endothelial disease, these cells do not function as well. Aging is known to induce and aggravate endothelial dysfunction, suggesting that endothelial dysfunction is unavoidable. One of the hallmarks of endothelial dysfunction is a decrease in the synthesis and availability of nitric oxide, which promotes dilation or relaxation of the blood vessels. Under normal conditions, nitric oxide significantly contributes to resting vasodilator tone and works to maintain a smooth and healthy vascular endothelium.

Dr. Pascal Bernatchez has uncovered a novel molecular approach that increases endothelial function and nitric oxide availability in aged vessels, while young vessels remain unaffected by the intervention. This suggests that there may be a molecular cause for how endothelial dysfunction develops. Bernatchez’s research will contribute to knowledge about how this approach restores endothelial function in an age-specific manner, how it regulates blood pressure and how endothelial dysfunction occurs. The findings may lead to novel therapeutic avenues for the range of cardiovascular diseases characterized by endothelial dysfunction.