AUTHOR=Kortekaas Rosa K. , Geillinger-Kästle Kerstin E. , Fuentes-Mateos Rocío , van Orsoy Roël , Al-Alyan Nakaa , Burgess Janette K. , Gosens Reinoud 

TITLE=The disruptive effects of COPD exacerbation-associated factors on epithelial repair responses

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1346491

DOI=10.3389/fimmu.2024.1346491

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Exacerbations of chronic obstructive pulmonary disease (COPD) increase mortality risk and can lead to accelerated loss of lung function. The increased inflammatory response during exacerbations contributes to worsening of airflow limitation, but whether it also impacts epithelial repair is unclear. Therefore, we studied the effect of the soluble factor micro-environment during COPD exacerbations on epithelial repair using an exacerbation cocktail (EC), composed of four factors that are increased in COPD lungs during exacerbations (IL-1β, IL-6, IL-8, TNF-α).</p></sec><sec><title>Methods</title><p>Mouse organoids (primary CD31-CD45-Epcam+ cells co-cultured with CCL206 fibroblasts) were used to study epithelial progenitor behavior. Mature epithelial cell responses were evaluated using mouse precision cut lung slices (PCLS). The expression of epithelial supportive factors was assessed in CCL206 fibroblasts and primary human lung fibroblasts. </p></sec><sec><title>Results</title><p>EC exposure increased the number and size of organoids formed, and upregulated <italic>Lamp3</italic>, <italic>Muc5ac</italic> and <italic>Muc5b</italic> expression in day 14 organoids. In PCLS, EC imparted no effect on epithelial marker expression. Pre-treatment of CCL206 fibroblasts with EC was sufficient to increase organoid formation. Additionally, the expression of <italic>Il33</italic>, <italic>Tgfa</italic> and <italic>Areg</italic> was increased in CCL206 fibroblasts from EC treated organoids, but these factors individually did not affect organoid formation or size. However, TGF-α downregulated <italic>Foxj1</italic> expression and upregulated <italic>Aqp5</italic> expression in day 14 organoids. </p></sec><sec><title>Conclusions</title><p>EC exposure stimulates organoid formation and growth, but it alters epithelial differentiation. EC changes the epithelial progenitor support function of fibroblasts which contributes to observed effects on epithelial progenitors.</p></sec>