Kynurenine acts as a signaling molecule to attenuate pulmonary fibrosis by enhancing the AHR-PTEN axis.
J Adv Res
; 2024 Jun 19.
Article
em En
| MEDLINE
| ID: mdl-38906325
ABSTRACT
INTRODUCTION:
Pulmonary fibrosis (PF) is a fatal fibrotic lung disease without any options to halt disease progression. Feasible evidence suggests that aberrant metabolism of amino acids may play a role in the pathoetiology of PF. However, the exact impact of kynurenine (Kyn), a metabolite derived from tryptophan (Trp) on PF is yet to be addressed.OBJECTIVES:
This study aims to elucidate the role of kynurenine in both the onset and advancement of PF.METHODS:
Liquid chromatography-tandem mass spectrometry was employed to assess Kyn levels in patients with idiopathic PF and PF associated with Sjögren's syndrome. Additionally, a mouse model of PF induced by bleomycin was utilized to study the impact of Kyn administration. Furthermore, cell models treated with TGF-ß1 were used to explore the mechanism by which Kyn inhibits fibroblast functions.RESULTS:
We demonstrated that high levels of Kyn are a clinical feature in both idiopathic PF patients and primary Sjögren syndrome associated PF patients. Further studies illustrated that Kyn served as a braking molecule to suppress fibroblast functionality, thereby protecting mice from bleomycin-induced lung fibrosis. The protective effects depend on AHR, in which Kyn induces AHR nuclear translocation, where it upregulates PTEN expression to blunt TGF-ß mediated AKT/mTOR signaling in fibroblasts. However, in fibrotic microenviroment, the expression of AHR is repressed by methyl-CpG-binding domain 2 (MBD2), a reader interpreting the effect of DNA methylation, which results in a significantly reduced sensitivity of Kyn to fibroblasts. Therefore, exogenous administration of Kyn substantially reversed established PF.CONCLUSION:
Our studies not only highlighted a critical role of Trp metabolism in PF pathogenesis, but also provided compelling evidence suggesting that Kyn could serve as a promising metabolite against PF.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Adv Res
Ano de publicação:
2024
Tipo de documento:
Article