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The role of alveolar epithelial type I cells in bleomycin-induced lung injury: Characterization of fibrosis-relevant signal pathways

Subject Area Pneumology, Thoracic Surgery
Term from 2017 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 373703964
 
Final Report Year 2023

Final Report Abstract

The focus of current research into the pathogenesis of pulmonary fibrosis is persistent alveolar epithelial damage with associated fibroblast proliferation. In the alveolar epithelium, three main types of intercellular junctional contacts exist that are involved in the formation of the apicoadherent contacts that separate the apical from the basolateral membrane, maintaining cell polarity and thus separating the external environment from the subepithelial tissue. We assume that all local cells of the lung parenchyma, especially the alveolar epithelium, are able to be involved in the pathomechanism of pulmonary fibrosis. In our project, we investigated the effect of the antifibrotic drug pirfenidone on the alveolar epithelium, particularly on the Fyn kinase, obtaining evidence for Fyn kinase activity in early fibrotic changes. High activity of Fyn kinase was measured in BLM-damaged cells, indicating an important function of Fyn in the development of pulmonary fibrosis. Previous findings also demonstrated that TGF-β-induced lung tissue damage in PCLS of WT mice leads to an increase in the protein content of α- and β-catenin and a decrease in E-cadherin. These studies strengthen the assumption that β-catenin is involved in the destabilization of adherens junctions (AJ) and thus in fibrotic remodeling processes in the alveolar epithelium via the downregulation of E-cadherin. Evidence further indicates that the inhibition of Fyn kinase is accompanied by an upregulation of the antifibrotic protein caveolin-1 (Cav-1) and an attenuation of the TGF-β signaling pathway, making the inhibition of Fyn kinase a promising novel target for the therapy for pulmonary fibrosis. In addition, the phosphorylation status of the p120Catenin protein was examined under early fibrotic conditions. An increase in p120Catenin-pY228 was detected under BLM and TGF-β treatment of NCI-H441 cells, which could not be detected in WT mouse lung tissue. P120Catenin pY904 increased under BLM treatment; under TGF-β treatment there was only an increase in the early phase. The change in phosphorylation of p120Catenin at the Tyr-904 residue therefore seems to be more relevant in the early phase under TGF-β damage and only regulated later under BLM. However, a reduction in p120Catenin pY904 was detectable in the WT mouse lung. Overall, the regulation of the phosphorylation status of p120Catenin in the tissue network appears to be influenced more complexly than in the pure alveolar epithelial cell line model. Additionally, to investigate the involvement of the alveolar epithelium, cell-cell contacts and known fibrotic signaling pathways, immunohistochemical studies were carried out on retrospective human lung samples. Acute courses of Covid-19 were compared with chronic courses. A control group with a cause of death of other origins and a group with interstitial lung disease (ILD) of other origins (negative Covid-19 or prepandemic time of death) served as further comparison groups. In the case of acute lung damage caused by a fulminant Covid-19 disease, diffuse alveolo-capillary lung damage occurs, such that the epithelial layer is destroyed. In the group of acute Covid-19 cases, a lower abundance of the protein βcatenin was measured and, in all disease groups in the study, a strong reduction in the protein amount of the transmembrane protein Junction Adhesion Molecule A (JAM-A), which is responsible for the integrity of the tight junction complexes, was measured.

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