Research Hanne Voet

Abstract

A recent Lancet commission highlighted the significant and increasing burden of chronic obstructive pulmonary disease (COPD) and the need for fundamental changes in the way we think about this disease. Currently, the diagnosis of COPD requires spirometric airway limitation (FEV1/FVC <70%). However, significant lung damage may already have occurred before abnormalities in lung function are identified. Recently, the term pre-COPD has therefore been proposed to refer to individuals without airflow obstruction, but who are at increased risk of subsequently developing COPD based on their symptoms, lung function, or structural abnormalities. Importantly, the pathophysiological mechanisms underlying pre-COPD are largely unknown. Recently, our research group demonstrated a >40% reduction of small airways in pre-COPD patients compared to healthy (smoking) controls, which was similar to established GOLD I COPD. In this project, the cellular and molecular mechanisms underlying structural abnormalities in pre-COPD will be extensively investigated, with a focus on inflammation and epithelial remodeling. A comprehensive strategy will be employed, entailing a thorough transcriptomics investigation and validation at the tissue level, complemented by functional experiments utilizing patient-derived bronchial epithelial cell cultures. Understanding early pathological changes in pre-COPD will ultimately enable earlier and improved diagnosis and therapeutic intervention in (pre-)COPD patients.

Researcher(s)

• Promoter: Lapperre Therese
• Co-promoter: Smet Annemieke
• Co-promoter: Verleden Stijn
• Fellow: Voet Hanne

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality. Acute exacerbations of COPD are heterogeneous and predominantly clustered in viral, bacterial, or eosinophilic exacerbations. Bronchial epithelial cells synthesise and release several proinflammatory mediators both constitutively and in response to these (non-)infective stimuli, thereby influencing inflammatory responses. The extend of these epithelial immunomodulatory responses may however differ with COPD disease severity and disease phenotypes. However, this has not been investigated before. In the present study we will develop in vitro human bronchial epithelial cell cultures from explant lungs from pre-COPD, mild to very severe COPD patients undergoing lobectomy or lung transplantation. Using micro-CT, in-depth characterization of ex-vivo morphology and loss of the small airways, extend of mucus plugging, and degree of emphysema will further phenotype COPD patients. Bronchial epithelial cell immunomodulatory responses to infective and non-infective triggers, including anti-viral responses and pro-inflammatory responses will be assessed in relation to disease severity (GOLD I-IV) and disease phenotypes (emphysema, mucus plugging, small airway loss). In addition, the relation between in vitro epithelial mucin expression and small airway mucus plugging will be explored. Improved understanding of these epithelial immunomodulatory responses to infective and non-infective triggers of exacerbations in relation to COPD disease severity and phenotypes may improve our understanding of COPD pathogenesis and may be important to develop targeted treatment options.

Researcher(s)

• Promoter: Lapperre Therese
• Fellow: Voet Hanne

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project