General Lung Disease Research Projects
Dr. Subash Sad
Mechanisms of host cell necrosis during pulmonary exacerbation in cystic fibrosis
Amount Awarded: $50,000
Cystic fibrosis (CF) is one of the most common genetic diseases with an incidence of around 1 in 2,500. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which impairs transport of chloride ions in cells. This results in dehydration of the airway mucus, progressive fibrosis and alteration in lung physiology. As a result, lungs of CF patients become highly susceptible to opportunistic bacterial infections. Up to 80% of CF patients become infected with P. aeruginosa, which accelerates the lung disease progression in children. Recurrent episodes of pulmonary (lung) symptoms termed “exacerbations” are very common in CF patients, which are associated with increased bacterial colonization, airway inflammation and decreased lung function. Aggressive antibiotic therapy during pulmonary exacerbations controls the disease, which suggests that pulmonary exacerbations are linked to bacterial infection. However, it is not clear how the chronic lung infection and the specific environmental triggers cause the switch to exacerbation.
Infection with virulent pathogens results in tissue necrosis, which can become fatal if not controlled early. Recently two major inflammatory cell death platforms termed inflammasomes and necrosomes have been discovered that are induced by the bacterial virulence factors, which synergistically cause rupture of infected cells, and massive induction of inflammation and tissue necrosis. We aim to decipher whether these inflammatory hubs promote pulmonary exacerbations of CF patients.
Our first aim is to isolate P. aeruginosa from the sputum of CF patients during the stable and exacerbation phases, and infect monocytes, neutrophils and epithelial cells with these bacteria. Monocytes and neutrophils will be directly purified from peripheral blood using labeled magnetic beads and primary epithelial cells will be obtained commercially. Activation of inflammasome/ necrosome platforms in infected cells will be evaluated by cell biological analysis (cell imaging, colorimetric and western blotting). Our second aim is to test the impact of P. aeruginosa on cells with a mutation in the CFTR gene.
Inflammasome and necrosome signaling of host cells is induced by the most virulent hub of the bacterium, the bacterial type III secretion system (T3SS). The bacterial isolates that we have obtained from the sputum of CF patients have all been sequenced. We will perform bio-informatic analysis of T3SS of P. aeruginosa isolated from CF patients to identify specific changes that occur during exacerbations.
The first innovation is the delineation of inflammatory cell death mechanisms during pulmonary exacerbations that lead to wide spread tissue necrosis. A second innovation is the use of clinical samples of P. aeruginosa that are all sequenced, and are isolated during the stable and exacerbation phase of CF. The third innovation is the evaluation of the diversity of all bacterial isolates in the sputum samples of CF patients for their impact on cell/tissue necrosis.
We study natural infections using bacteria that are isolated from CF patients. We evaluate the mechanisms that induce tissue necrosis in the lungs. We also evaluate the impact of host mutation on induction of cell necrosis. We anticipate that our research outcomes will shift the field towards systemic analysis of inflammatory cell death platforms in CF pathogenesis, which will lead to the discovery of new therapeutic approaches.
Dr. Kjetil Ask
The role of DECTIN-1 in pulmonary fibrosis
Amount Awarded: $50,000
Lung fibrosis is a disease that often proves fatal 2-3 years post-diagnosis. It affects about 15,000 Canadians with approximately 6,000 new diagnoses made each year. As the disease progresses, scar tissue accumulates in the lungs, making breathing difficult and then impossible. There are few treatment options for this type of disease. The reason for this is likely because we do not know well how people develop the disease in the first place and we know very little about how and why the scarring is out of control. If we can better understand which cells are responsible for making the scars and how they produce the scars, then we may be able to stop the scarring process so patients can breathe better and live longer.
Our project aims to understand the molecular processes leading to the generation of a specialized cell type called the macrophage. We think that under certain circumstances, macrophages are very important in the scarring process and that they contribute to the formation of the scars in the lungs. Our main objective is to provide scientific evidence that they are truly involved and required for the scarring process, and to better understand how they do it. If we can increase our understanding of the molecular mechanisms driving this process and demonstrate that this cell is critical for the scarring process, then we can perhaps stop the scarring process and help patients to breathe better and improve their quality of life.
We have already identified a key molecular mechanism and what we think is the most important cell – the macrophage. We have also identified a unique marker of this important cell. Here, we will continue this work and clarify if the unique marker is also actively involved in the fibrotic process. By examining the specific role of this molecule, we believe we can identify a novel therapeutic target required in the scarring process.
Our project is unique because we are exploring a molecular mechanism that is well-known in other cell types but that has never been shown to be important in macrophages or in lung fibrosis. Our research will help to further understand the role of activated macrophages in pulmonary fibrosis. Though our projects described in this application are focused on lung fibrosis, these mechanisms are likely to have similarities with those in other chronic lung diseases that have components of scarring associated with their disease such as asthma (airway fibrosis) and COPD (bronchial fibrosis). If we can further our understanding on how macrophages contribute to the scarring process and if they are essential for this process, we can perhaps find new treatment options for patients with fibrotic lung disorders.
Dr. Clodagh Ryan
Effect of Continuous Positive Airway Pressure on Cardiopulmonary Function in Pulmonary Hypertension
Amount Awarded: $50,000
Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary condition with a female predominance affecting approximately 50 per million. It is caused by progressive narrowing and constriction of the small pulmonary vessels, leading to an increase in the afterload to the naïve right ventricle (RV), eventually leading to RV failure and death. Significant advances in the treatment of PAH have occurred over the last 10 years with the development of a number of PAH specific medications.
These medications improve morbidity and exercise tolerance and can lead to a reduction in RV afterload and improvement in RV function. Recent registry data show an improvement in survival with current medical therapies from a 3 year survival of 34% in the 1980’s to 70 – 83% in treated patients today. As survival improves in this population, there are increasingly older patients with more comorbid illnesses and obesity. Sleep apnea is more prevalent in those with obesity and occurs in approximately 20 – 40% of patients with PAH. Obstructive sleep apnea events generate negative intrathoracic pressure, intermittent hypoxia and arousals which can adversely impact heart function. Continuous positive airway pressure (CPAP) is the gold standard treatment of obstructive sleep apnea. Nevertheless, it is recognized that CPAP can have both positive and occasionally negative impacts on heart function depending on the underlying cardiac condition. In heart failure patients, the preload- and afterload-dependent status will determine the cardiac output responses (increase or decrease). Therefore, CPAP could improve and augment right heart function in patients with PAH. However, no previous studies have specifically examined the impact of CPAP in those with PAH, nor the acute effects of obstructive apneas.
Objectives of the project:
- To evaluate the acute effects of CPAP on the right heart function in patients with PAH compared to healthy controls.
- To assess the acute effects of simulated obstructive apneas on right heart function in patients with PAH compared to healthy controls.
Patients with pulmonary artery hypertension who consent and are undergoing a clinically necessary right heart catheterization test, and healthy volunteers will be tested to determine the impact of CPAP and simulated obstructive apneas on RV function in the catheterization laboratory.
Neither the acute impact of CPAP on RV function, nor the effect simulated obstructive apneic effects has been evaluated in patients with pulmonary artery hypertension. Our project is evaluating a device therapy that if found to be beneficial has the potential to provide an additional treatment that could significantly improve lung-heart function for those suffering from PAH. All too often due to deteriorating lung function these patients become oxygen dependent and exercise limited. CPAP if beneficial is readily available and relatively inexpensive therapy.
Dr. Mandeep Singh
The variability and impact of segmental neck and leg fluid volume shifts on upper airway collapse and obstructive sleep apnea (OSA) severity in surgical patients with OSA– A two-center, prospective cohort study
Amount Awarded: $49,984
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, associated with repeated upper airway collapse and reduced blood oxygen levels. At the time of surgery, exposure to general anesthesia and narcotic medications can lead increased respiratory problems poor surgical results, respiratory failure and even death. Experts from surgery, anesthesia and the perioperative team have established good practices and guidelines called the Enhanced Recovery After Surgery (ERAS). It is recommended that fluid administration should be done with care but no specific criteria for OSA patients is laid out. We know that increased lung fluid volume leads to problems in oxygen levels in blood and breathing problems especially after chest and abdominal surgeries. Similarly, upper airway collapse can occur more frequently in OSA patients as increased fluid in neck structures can compress the upper airway, leading to worsening of OSA and increased respiratory complications following surgery.
Our study objectives are to measure changes occurring in the fluid volumes in the neck, legs and total body, and find a relation between these changes and worsening of obstructive sleep apnea in patients undergoing general anesthesia and receiving intravenous fluids.
We will include 50 patients undergoing various types of surgeries (except heart, spine or neck surgeries), and measure fluid volumes using bioelectrical impedance technology, before and after surgery. Patients will also undergo portable sleep studies to look at the impact on their OSA status. All the measurements and study events will be collected in a well detailed, prospective fashion. We will also collect clinical findings such as respiratory complications associated with OSA patients, e.g. stay in the recovery room, respiratory failure, and stay in the intensive care unit.
In this novel study, we will extend our group’s previous research work evaluating the impact of fluid shifts on OSA severity. Our group has a strong track-record in screening, diagnosing, and evaluating perioperative outcomes of OSA patients. Furthermore, recently we have established a protocol to diagnose and screen OSA patients, as well as measure postoperative fluid measurements in patients undergoing surgery. Our study will be the first to evaluate and establish the relationship between fluid administration and worsening OSA severity in this patient population. Our findings will establish a key link between OSA worsening, increased postoperative respiratory complications in OSA patients and fluid changes that occur after surgery. Our findings will also inform the ERAS guidelines and establish evidence based standards in fluid management of OSA patients undergoing surgery.
OSA patients are exposed to increased risk of respiratory complications following surgery and anesthesia leading an increased burden of care, and poor clinical outcomes. The findings of our study will aim to minimize patients undergoing surgery from developing respiratory complications, enhance their postoperative recovery and result in improved overall lung health.
Dr. Chung-Wai Chow
Impulse Oscillometry for Early Detection of Small Airway Obstruction
Amount Awarded: $50,000
Many airway diseases such as bronchiolitis obliterans, asthma and chronic obstructive lung disease (COPD) begin in the small airways, an area known as the ‘silent zone’ as changes in small airway function are not detected by available diagnostic tests. Conventional pulmonary function tests (cPFT), with spirometry and FEV1 (forced expiratory volume in 1 sec), is the gold standard metric of lung function. However, FEV1 is largely sensitive to central airway obstruction 1,2 and cannot detect changes in the small airways until 75% of all the small airways are occluded 3,4. In the context of lung transplant (LTx) where graft function is critically impacted by small airway function, spirometry is used to monitor development of acute rejection (AR) and chronic lung allograft dysfunction (CLAD) although it is known that both begin in the small airways. AR occurs in 30-50% of patients within the first year post-LTx5,6, and is the single highest risk for development of CLAD. CLAD develops in 50% of all LTx recipients by year 5, and is the major impediment to long-term survival post-LTx6.
Unsurprisingly, spirometry has only a 60% sensitivity for detecting clinically significant AR7. Bronchoscopy with transbronchial biopsies (TBBx) is also routinely conducted post-LTx. However, TBBx usually only contains a few small airways and is associated with complications such as bleeding and pneumothorax8 . Further, it has a discovery rate of AR of only 47-57%9-11. Forced oscillometry (FO) is a simple PFT that directly assesses small airways. It detects lung function changes earlier than cPFT in COPD12 and found to be a better metric of asthma control in children13,14. While spirometry is a forced manoeuver1,2, FO is conducted during normal breathing and requires minimal patient cooperation, an advantage early post-LTx, where chest discomfort is common.
We posit that FO detects airflow obstruction with a greater sensitivity than cPFT, FEV1 and TBBx following LTx. Therefore, lung function monitoring with FO will lead to earlier diagnosis of AR and CLAD, with the potential for earlier intervention and better clinical outcomes. The overall goal of the research programme is to compare the sensitivity of FO with cPFT in detection of CLAD post-LTx.
The goal of the current proposal is to conduct a study to compare FO with spirometry and FEV1 in detecting AR during the first 18 months post-LTx, a period when the incidence of AR is high. We will build on a pilot study already underway that is enrolling 80 new double LTx recipients for FO testing, with follow-up of only 3 months. The current study will prolong follow-up to 18 months and increase the sample size to 100. All LTx patients are evaluated with weekly outpatient cPFT at University Health Network (UHN) for the initial 3 months post-LTx. Thereafter, cPFT are conducted at UHN during assessment visits at 3, 6, 9, 12, 18 and 24 month post-LTx. We will conduct FO prior to each routine post-LTx cPFT at UHN; this study design allows for comparison of paired FO and spirometric measurements for every time-point for all patients. We will also collect clinical data that affect lung function; these include human leukocyte antigen matching, TBBx findings and infections. The statistical analysis will be conducted in collaboration with the Biostatistics Research Unit at UHN (https://thebru.ca/). Correlations between repeated measures will be conducted according to the methods of Bland and Altman15,16 to assess the significance of correlations between oscillometric and spirometric parameters, as well as these parameters with clinical and histological diagnosis of AR.
This is the first study to directly compare FO with spirometry post-LTx, a clinical scenario where development of small airway obstruction is a predictable event. As such, it is an almost perfect clinical model to compare the sensitivity of FO with FEV1 in detecting small airway obstruction. Our research is expected to offer robust data to support the use of FO for monitoring of small airway disease for multiple etiologies, and thus lead to earlier diagnosis of AR post-LTx as well as more common diseases such as COPD and asthma, and in this way, improve lung health in Canada.
A major gap was revealed when cannabis became legal in Canada: the lack of scientific research about how using it affects your health. The Lung Health Foundation has joined forces with an industry partner to fill that gap by funding a research program that investigates various health impacts of cannabis use – whether used recreationally or as a medical option for chronic disease pain management and treatment. It’s another way we’re using research and innovation to protect your breath.