Abstract
The T helper 2 (Th2) inflammatory cytokine interleukin-13 (IL-13) has been associated with both obstructive and fibrotic lung diseases; however, its specific effect on the epithelial stem cells in the gas exchange compartment of the lung (alveolar space) has not been explored. Here, we used in vivo lung models of homeostasis and repair, ex vivo organoid platforms, and potentially novel quantitative proteomic techniques to show that IL-13 disrupts the self-renewal and differentiation of both murine and human type 2 alveolar epithelial cells (AEC2s). Significantly, we find that IL-13 promotes ectopic expression of markers typically associated with bronchiolar airway cells and commonly seen in the alveolar region of lung tissue from patients with idiopathic pulmonary fibrosis. Furthermore, we identify a number of proteins that are differentially secreted by AEC2s in response to IL-13 and may provide biomarkers to identify subsets of patients with pulmonary disease driven by "Th2-high" biology.
Highlights
Chronic lung diseases are associated with significant morbidity and mortality and, collectively, constitute the fourth leading cause of death in the United States
We used a combination of in vivo lineage tracing in an injury/repair model, ex vivo organoid culture, and quantitative proteomics to reveal previously unappreciated STAT6-dependent effects of the T helper 2 (Th2) cytokine, IL-13, on alveolar epithelial stem cells
Our in vivo lineage-tracing experiments clearly showed that IL-13 causes impaired differentiation of AEC2s to AEC1s in the PNX model of compensatory lung regrowth, suggesting that IL-13 can affect the stem cell responses of the alveolar epithelium
Summary
Chronic lung diseases are associated with significant morbidity and mortality and, collectively, constitute the fourth leading cause of death in the United States. Chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis are 2 such diseases with increasing prevalence Both conditions involve pathological changes in the gas exchange (or alveolar) region of the lung, which normally consists of a delicate arrangement of thin-walled air sacs with type 1 and type 2 alveolar epithelial cells (AEC1s and AEC2s), stromal cells, and blood vessels. Lung fibrosis is typically associated with the appearance in the alveoli of tracts of epithelial cells expressing ectopic markers. Such tissue includes hyperplastic type 2 pneumocytes lining alveolar septae [1, 2] and the “bronchiolarized” epithelium typically present in areas of honeycomb cysts [3], the variably sized cystic structures found in scarred areas of lung in advanced pulmonary fibrosis
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