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Beneficial Effects of Tanimilast and Formoterol on Mouse Lung Epithelial Progenitors In Vitro

ABSTRACT: Background: The progressive decline of lung function in chronic obstructive pulmonary disease (COPD) is driven by exacerbations, during which inflammation leads to impaired lung regeneration. Dysfunctional lung epithelial cells contribute to defective repair and tissue remodelling. This study explored regeneration and differentiation mechanisms, focusing on the cAMP pathway, and whether targeting this pathway with the phosphodiesterase 4 (PDE4) inhibitor Tanimilast and the β2 adrenoceptor agonist Formoterol could promote lung repair in vitro. Methods: A mouse lung organoid model and precision-cut lung slices (PCLS) were used to assess the regenerative potential of Tanimilast and Formoterol. In lung organoid studies, injury was induced by cigarette smoke extract (CSE) exposure. In PCLS, injury was induced by treatment with elastase. RNA-sequencing (RNA-seq) was used to identify transcriptional changes. Results: CSE exposure resulted in reduced organoid formation efficiency compared to air-exposed controls. Both combined and single treatments with Tanimilast and Formoterol increased organoid numbers compared to controls, with the most pronounced effect observed in CSE-exposed lung organoids. In PCLS, Tanimilast and Formoterol inhibited negative effects of elastase on alveolar airspace size. Under combined treatment with Tanimilast and Formoterol, RNA-seq analysis revealed positive enrichment of genes involved in epithelial cell differentiation and positive enrichment of genes encoding secreted factors involved in epithelial-mesenchymal signalling in lung fibroblasts, which was strongest in cultures exposed to CSE. Conclusion: Our findings indicate that the combination of Tanimilast and Formoterol, likely through a cAMP mechanism, reverses both the negative effects of CSE on lung organoid formation and the negative effects of elastase on alveolar airspace enlargement in vitro implying beneficial effects in lung regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE308926 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:The transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR. To test this hypothesis, PCLS obtained from livers of wild type mice (WT-PCLS) and Fxr-knockout mice (FXRKO-PCLS) were treated with 40µM CsA for 24h and 48h. ATP and histological assays were applied to assess the viability of PCLS. DNA microarrays combined with bioinformatics analysis were used to identify genes and processes that were affected by CsA in WT-PCLS and/or FXRKO-PCLS. In addition, WT-PCLS and FXRKO-PCLS were exposed to the endogenous FXR ligand chenodeoxycholic acid (CDCA) and subjected to q-PCR to determine whether subsets of known FXR-targets and the identified genes were regulated upon FXR activation in an FXR-dependent manner. No difference in viability was observed between WT-PCLS and FXRKO-PCLS upon CsA treatment. Transcriptomics data analysis revealed that CsA significantly upregulated stress-response and inflammation and significantly downregulated processes involved in lipid and glucose metabolism in both WT-PCLS and FXRKO-PCLS. However, only in FXRKO-PCLS, CsA upregulated additional pro-inflammatory genes and downregulated genes related to mitochondrial functions. Furthermore, only in WT-PCLS, CDCA upregulated a subset of known FXR-target genes as well as the regulator of inflammation and mitochondrial functions peroxisome proliferator- activated receptor delta (Ppar delta). Although FXR governs energy metabolism, no major differences in response to CsA could be observed between WT-PCLS and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism. This finding indicates that CsA does not directly affect FXR functions in relation to the above mentioned processes. However, the more pronounced induction of pro-inflammatory genes and the downregulation of genes involved in mitochondrial functions only in FXRKO-PCLS suggest that FXR deficiency aggravates CsA-induced inflammation and impairs mitochondrial functions. Therefore, FXR can exert its hepatoprotective functions by controlling inflammation and mitochondrial functions, possibly involving an FXR-PPAR delta cross-talk. Precision cut liver slices (PCLS) obtained from livers of wild type (WT) and farnesoid X receptor knockout (FXRKO) mice were exposed for 24 hours to 40uM of CyclosporinA (CsA).

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Beneficial Effects of Tanimilast and Formoterol on Mouse Lung Epithelial Progenitors In Vitro

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