Visualizing undetectable disease in asthma

Aileen Hsieh was a semi-finalist in the 2022 UBC Three Minute Thesis (3MT) competition. Aileen presented their research, "Visualizing Undetectable Disease in Asthma.” They hope to explore new techniques to develop better drugs to enable millions of patients with asthma to breathe more easily. Aileen Hsieh is completing their Master of Science in Pharmacology in the Faculty of Medicine at the University of British Columbia under the supervision of Dr. Tillie-Louise Hackett.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofUnreviewedGraduat

The Role of miRNAs in Extracellular Matrix Repair and Chronic Fibrotic Lung Diseases

The lung extracellular matrix (ECM) plays a key role in the normal architecture of the lung, from embryonic lung development to mechanical stability and elastic recoil of the breathing adult lung. The lung ECM can modulate the biophysical environment of cells through ECM stiffness, porosity, topography and insolubility. In a reciprocal interaction, lung ECM dynamics result from the synthesis, degradation and organization of ECM components by the surrounding structural and immune cells. Repeated lung injury and repair can trigger a vicious cycle of aberrant ECM protein deposition, accompanied by elevated ECM stiffness, which has a lasting effect on cell and tissue function. The processes governing the resolution of injury repair are regulated by several pathways; however, in chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) these processes are compromised, resulting in impaired cell function and ECM remodeling. Current estimates show that more than 60% of the human coding transcripts are regulated by miRNAs. miRNAs are small non-coding RNAs that regulate gene expressions and modulate cellular functions. This review is focused on the current knowledge of miRNAs in regulating ECM synthesis, degradation and topography by cells and their dysregulation in asthma, COPD and IPF.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofReviewedFacultyResearche

The Role of the Dynamic Lung Extracellular Matrix Environment on Fibroblast Morphology and Inflammation

The extracellular matrix (ECM) supports lung tissue architecture and physiology by providing mechanical stability and elastic recoil. Over the last several decades, it has become increasingly clear that the stiffness of the ECM governs many cellular processes, including cell-phenotype and functions during development, healing, and disease. Of all the lung ECM proteins, collagen-I is the most abundant and provides tensile strength. In many fibrotic lung diseases, the expression of collagen is increased which affects the stiffness of the surrounding environment. The goal of this study was to assess the effect on fibroblast morphology, cell death, and inflammation when exposed to 2D and 3D low (0.4 mg/mL) versus high (2.0 mg/mL) collagen-I-matrix environments that model the mechanics of the breathing lung. This study demonstrates that human fetal lung fibroblasts (HFL1), grown in a 3D collagen type-I environment compared to a 2D one, do not form cells with a myofibroblast morphology, express less F-actin stress fibers, exhibit less cell death, and significantly produce less pro-inflammatory IL-6 and IL-8 cytokines. Exposure to mechanical strain to mimic breathing (0.2 Hz) led to the loss of HFL1 fibroblast dendritic extensions as well as F-actin stress fibers within the cell cytoskeleton, but did not influence cytokine production or cell death. This dynamic assay gives researchers the ability to consider the assessment of the mechanodynamic nature of the lung ECM environment in disease-relevant models and the potential of mechano-pharmacology to identify therapeutic targets for treatment.Medicine, Faculty ofScience, Irving K. Barber Faculty of (Okanagan)Non UBCAnesthesiology, Pharmacology and Therapeutics, Department ofBiology, Department of (Okanagan)ReviewedFacultyResearcherOthe

Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study

Background: the concept that the small conducting airways <2mm in diameter become the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD) is well established in the literature. It has also been shown that the last generation of small conducting airways, terminal bronchioles, are significantly destroyed in patients with very-severe COPD. What is not known is at what stage in the development of COPD the loss of small airways occurs, or how loss of terminal and transitional (first generation of respiratory airways) bronchioles - relates to the loss alveolar surface area that characterizes emphysema. Methods: a novel multi-resolution computed tomography (CT) imaging protocol was applied to systematically, randomly sampled whole lungs or lobes of smokers with normal lung function (n=10), mild (n=10), moderate (n=8), and very-severe COPD (n=6). The 34 lung specimens provided 262 lung tissue samples for stereological assessment of the number and morphology of terminal and transitional bronchioles, airspace size (Lm), alveolar surface area. Findings: the new data demonstrate that 41% of terminal bronchioles, 57% of transitional bronchioles, and 37% of the alveolar surface area is lost in patients with mild and moderate COPD compared to control smokers, before any emphysematous changes can be detected by CT. We also show these pathological changes correlate with lung function decline. Importantly, we demonstrate that loss of terminal and transitional bronchioles occurs in regions of the lung that have no loss of alveolar surface area. Further, we validated using histology, that the surviving small airways have thickened walls and narrowed lumens which become more obstructed as the disease progresses. Interpretation: these data demonstrate that small airways disease is an early pathological feature in mild and moderate COPD. Importantly, this study emphasises that early intervention in mild and moderate COPD patients is most likely required for disease modification

Epithelial-interleukin-1 inhibits collagen formation by airway fibroblasts: Implications for asthma

In asthma, the airway epithelium has an impaired capacity to differentiate and plays a key role in the development of airway inflammation and remodeling through mediator release. The study objective was to investigate the release of (IL)-1 family members from primary airway epithelial-cells during differentiation, and how they affect primary airway fibroblast (PAF)-induced inflammation, extracellular matrix (ECM) production, and collagen I remodeling. The release of IL-1α/β and IL-33 during airway epithelial differentiation was assessed over 20-days using air-liquid interface cultures. The effect of IL-1 family cytokines on airway fibroblasts grown on collagen-coate

Genomewide Clonal Analysis of Lethal Mutations in the Drosophila melanogaster Eye: Comparison of the X Chromosome and Autosomes

Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes