Dr. Roma Sehmi
Role of TL1A/Death Domain Receptor 3 (DR3) axis in the activation of ILC2 in Asthma
Amount Awarded: $50,000
Asthma is a chronic disease of the airways that affects more that 3 million people in Canada and it’s incidence is increasing. 1 in 3 individuals in Ontario will receive a physician diagnosis of asthma during their lifetime. Despite the development of anti-asthma drugs, many asthmatics continue to have worsening breathlessness as they age. Investigating biological processes that cause the symptoms of asthma may reveal new drug targets to treat uncontrolled breathlessness that worsens over time in asthmatics.
After asthmatics inhale particles to which they are allergic, their lungs become inflamed and their asthma worsens. During this process, recruitment to the lung of mature cells such as eosinophils and basophils and their precursor cells occurs. These cells, when activated release cell-derived products which damage the lung tissue and symptoms of asthma develop such as airway narrowing and mucus over production. Identifying factors/cells that promote and expand eosinophil numbers in the airways may provide a valuable target for treatment of asthma. In the last decade, a novel group of cells termed “Group 2 innate lymphoid cells (ILC2s)” have been discovered as a major tissue source of factors that promote eosinophil growth, recruitment and activation in the lung tissue. In asthma our group has found that ILC2 producing pro-eosinophilic cytokines are increased in the airways in patients with uncontrolled symptoms despite high doses of steroids. As well, we reported that ILC2 provide the initiation signal for allergic asthmatic responses. Little however is known about all the factors that recruit and activate ILC2 in asthmatic airways. This project will investigate the role of a factor known as tumor necrosis like factor 1A (TL1A) and changes in its receptor (death receptor 3; DR3) expression on ILC2 in the airways in asthmatic responses. We will test the effect of corticosteroids, the gold-standard for treatment of asthma, on DR3 expression on ILC2.
Using an allergen exposure model that is well established in our laboratory, we will study subjects who are induced to have an asthmatic response as a result of a controlled inhalation of a compound to which they are allergic. By taking sputum samples coughed up from the airways, level of expression of DR3 on ILC2 cells and amount of TL1A in sputum will be assessed. The time points chosen to sample sputum before and after allergen challenge are well defined as time points at which maximum increases in airway eosinophil numbers occur. We will investigate expression levels of DR3 on ILC2 from sputum (a) before and after an allergic asthmatic response, (b) compare these changes with cell types that produce eosinophil growth factors such as T cells, and (c) by isolating ILC2s from blood (as these are too rare to isolate from sputum), we will investigate what effect this receptor has on ILC function and the ability of corticosteroids to interfere with this effect. Effects on ILC2s will be compared to T cells, as the latter are known to be steroid sensitive cells.
Animal studies show that ILC2 are an important local source of growth factors that promote expansion of cells that cause many of the symptoms of asthma. Understanding the role of ILC2 in human eosinophilic asthma is a new and important field. By comparing activation of ILC2s and T cells, and investigating the effect of known drugs on modulating this activation, this study will provide unique drug targets that may be beneficial in asthmatics who continue to have uncontrolled symptoms despite being treated with high doses of corticosteroids.
Increased numbers of eosinophils is a prominent feature of the asthmatic lung and studies have shown that this feature increases as the symptoms of this disease worsen. By understanding the role of cells that promote the persistence of eosinophils in the lung, we aim to better treat this condition.
Dr. Azadeh Yadollahi
Investigating whether Bronchodilator Medications can Prevent Effects of Rostral Fluid Shift on Airway Narrowing in Asthma
Amount Awarded: $50,000
Asthma affects 8% of Canadians and its health related costs are $600M annually. Nocturnal exacerbation of asthma is a clinically important phenotype of asthma and is common in two-thirds of asthma patients. Nocturnal asthma is associated with increased use of asthma medication, more severe asthma symptoms, and greater asthma related morbidity and mortality. The recumbent posture and sleep increase lower airways narrowing and nocturnal asthma.
Emergency visits due to asthma exacerbation, calls to physicians, and death due to asthma are more common during the night. Despite optimum treatments, nocturnal symptoms remain a major concern and mechanisms accounting for nocturnal asthma remain unclear. We propose that lying down during sleep causes shifts of body fluids from the legs to the chest and neck, and this rostral fluid shift exacerbates narrowing of small airways in lungs in patients with asthma. Fluid accumulation in the chest can increase bronchial blood volume, narrow the airway lumen, and thus contributes to asthma severity and fatality.
Our objective is to demonstrate that in patients with nocturnal asthma, bronchodilating medications do not prevent the airway narrowing due to fluid shift. Asthmatics with and without nocturnal asthma will be randomized to receive placebo or bronchodilator. Then, they will lie supine for 30 minutes and their legs will be squeezed for 25 minutes (from 5 mins to 30 mins) to increase fluid shift out of the legs and simulate the amount of fluid shift that occurs at night. A week later they will be crossed over to the other study arm. In both study arms, we will measure fluid volumes in the leg and chest, and airway resistance at 0 min and 30 min. We expect that in patients with nocturnal asthma, even with bronchodilator treatment, increased fluid shift into the chest will increase airway resistance.
Post-mortem analysis of the lungs show that airway walls are thicker in asthmatics who died from fatal asthma attacks than from other causes. Acute changes in airway wall thickness can occur from local edema due to vascular leakage in the airway wall. One of the principal mechanisms by which increased excess airway fluid can increase airway resistance is through entering the airway adventitia, swelling the airway wall and decreasing the airway lumen. As this mechanism is independent of contraction of the airway smooth muscle, it would not be expected that it would be prevented by bronchodilating medication. Demonstrating this is of clinical relevance, as long acting bronchodilating medication in combination with inhaled steroids is the principle component of current guidelines for the prevention of nocturnal asthma. With this proposal, we intend to demonstrate that bronchodilating treatment does not address all mechanisms of nocturnal airway narrowing in asthma.
This research addresses physiological mechanisms that apply to an important clinical problem. Understanding the mechanisms of lower airway narrowing due to fluid shift will facilitate development of new treatments for nocturnal asthma by reducing fluid shifts and their pernicious effects. These treatments can be as simple and practical as use of compression stockings during the day, exercise, diuretics, or head elevation during sleep. If supported by the data, this practicality, together with their translational impact, would comprise the greatest strengths of this research.