Center for Translational Pediatric Pulmonology
*Modelling the bronchial epithelium in children*

Many respiratory diseases, such as asthma, severe preschool wheeze, cystic
fibrosis and even low lung function predisposing to COPD, arise in the first
years of life. These diseases are the outcome of the interaction of a
genetically susceptible host with a permissive environment. Most lung diseases
can therefore be conceived as a developmental disease, as these arise in a
child with a developing lung and immune system. The bronchial epithelium is a
key cell orchestrating the response of the airways and the immune system, and
bronchial epithelial cells express many respiratory disease genes.
We hypothesize that curative, early life treatment for lung disease needs to be
based on detailed, mechanistic insights into the inception of disease in the
bronchial epithelium rather than established disease in adults. To identify
these *early mechanisms*, we will need to study children, investigate cells
from the bronchial airways, and develop models that reflect bronchial
epithelial cell function. However, performing invasive research in children is
limited by ethical constraints, so we will need to develop and validate models
that do not pose a burden on the child. In contrast to the bronchial
epithelium, the nasal epithelium is accessible in young children. However, it
is not known how well the upper airway reflects the lower airways in children
with different disease conditions.

The main objective of our Center for Translational Pediatric Pulmonology
(CTPP) is to establish models of bronchial epithelial function in children, by
(1) epithelial organoid cultures derived from bronchial epithelial cells; (2)
bronchial brushings; and (3) nasal brushings. These models will be validated by
comparison of gene expression from epithelial cells of these three models to
the gold standard: bronchial (single cell) gene expression in bronchial airway
biopsies. Furthermore, this will enable future mechanistic and intervention
studies, as it will be known which aspects of the bronchial epithelium will be
reflected in nasal cells, and which are retained in epithelial organoid cell
culture.

Observational, cross-sectional cohort study

Ethical concerns are highly relevant when performing invasive research in
children. We propose to perform research in (young) children, who already
undergo bronchoscopy for clinical indications. During bronchoscopy the major
risk is that of anesthetics. It has been well documented that risks related to
a bronchoscopy (biopsy and brushings) itself are limited to the incidental need
for bronchodilators, minor bleeding that always stopped spontaneously, and
fever. The main ethical aspect of our project therefore is obtaining (extra)
primary bronchial epithelial and nasal cells for research purposes, which will
prolong the planned bronchoscopy with 5 - 10 minutes. The benefits of this
research will relate to the validation of less or non-invasive methods to study
primary and cultured airway epithelial cells in children, which may reduce the
need for future invasive studies.