Epithelial-Interleukin-1 Inhibits Collagen Formation by Airway Fibroblasts: Implications for Asthma
This week we profile a recent publication in Scientific Reports from Dr. Emmanuel Osei (pictured)
in the laboratory of Dr. Tillie-Louise Hackett at the Centre for Heart Lung Innovation.
Can you provide a brief overview of your lab’s current research focus?
Dr. Emmanuel T. Osei is a postdoctoral fellow in the laboratory of Dr. Tillie-Louise Hackett, Associate Professor, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia and a Principal Investigator at the Center for Heart Lung Innovation, St. Paul’s Hospital. Dr. Hackett’s research program is focused on understanding the disruption of normal repair processes within the lung epithelial-mesenchymal trophic unit (EMTU) and how this propagates inflammation and tissue remodelling in patients with asthma and chronic obstructive pulmonary disease (COPD). Her laboratory uses ultra-resolution imaging to identify early disease lesions and human in vitro models to investigate the underlying cellular, molecular, and genetic abnormalities responsible for disease pathobiology. The objectives of the research program are to provide new approaches to diagnose and discover new treatments to improve the quality of life of asthma and COPD patients.
What is the significance of the findings in this publication?
Dr. Osei’s work has focused on establishing complex 3-dimentional (3D) in vitro models to understand how abnormal communication between lung epithelial and mesenchymal cells contributes to asthma and COPD pathogenesis. During Dr. Osei’s PhD, the group discovered that the lung epithelium releases interleukin (IL)-1α, a master-regulatory cytokine that controls lung fibroblast mediated inflammation and extracellular matrix production and homeostasis (Osei et al., 2016 ERJ, 48(2): 359-369).
In the recent study, Osei et al., (Sci Rep 2020 10(0): 8721), found that there was increased release of IL-1α and its family member IL-1β during the early stages of differentiation of airway epithelium from asthmatic patients compared to healthy individuals. In asthma, the airway epithelium plays a key role in airway inflammation and remodelling, through signalling which recruits and activates immune cells, and resident tissue mesenchymal cells. The authors found that IL-1α/β induce airway fibroblasts to release pro-inflammatory cytokines (IL-6, IL-8, TSLP and GM-CSF). These cytokines are known to be vital for allergic sensitization, smooth muscle cell-hypercontractility and airway hyperresponsiveness as well as increased influx of eosinophils and TH2-driven inflammation in asthma. They also found that IL-1 inhibited the ability of airway fibroblasts to repair collagen I fibers leading by Lysyl oxidase (LOX) and Lysyl oxidase like (LOXL) enzymes 1 and 2. This is noteworthy since the group recently demonstrated using non-linear optical microscopy that the extensively deposited collagen in asthmatic airways associated with airway remodelling, is structurally highly disorganized in asthmatic lungs irrespective of age, sex, and disease severity (Mostaco-Guidolin and Osei et al., AJRCCM 2019).
These findings point to a role for IL-1α/β in both inflammation and collagen disorganization that may contribute to airway remodeling and shows that although it is important to target chronic inflammation in asthma as most clinical trials have done, the assessment of airway remodeling as a clinical endpoint in trials is also vital.
What are the next steps for this research?
There are currently no treatments that modify airway remodeling in asthma. As the structural features of the ECM are known to influence cellular programming, understanding the biophysical properties of ECM proteins like collagen within the lung will be an important step forward to understanding asthma pathogenesis. Dr. Osei is now working on a 3D model that enables the application of mechanical strain to the ECM environment of cells to mimic the normal breathing lung and during an asthma episode. The goal is to identify druggable targets involved in airway-fibroblast-ECM interactions in the asthmatic airways that can help modify airway remodelling in asthma.
This work was funded by:
This work was funded by Dr Hackett’s unrestricted research grant from the Canadian Institutes of Health Research (CIHR) operating grant (MOP 1305040).
Dr. Osei holds a Michael Smith Foundation for Health Research (MSFHR) and MITACS Accelerate postdoctoral fellowships.
Dr. Hackett holds a CIHR New Investigator award, MSFHR Scholar award, Providence Health Care Investigator award, and is a Parker B Francis fellow.