Aggravation of pulmonary fibrosis after knocking down the aryl hydrocarbon receptor in the insulin-like growth factor 1 receptor pathway.
Br J Pharmacol
; 179(13): 3430-3451, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35083738
ABSTRACT
BACKGROUND AND PURPOSE:
Idiopathic pulmonary fibrosis is a devastating disease with multiple contributing factors. Insulin-like growth factor 1 receptor (IGF1R), with a reciprocal function to aryl hydrocarbon receptor (AhR), is involved in airway inflammation. The exact relationship between IGF1R and AhR in lung fibrogenesis is unclear. This study aimed to investigate the cascade pathway involving IGF1R and AhR in idiopathic pulmonary fibrosis. EXPERIMENTALAPPROACH:
The AhR and IGF1R expressions were determined in the lungs of idiopathic pulmonary fibrosis patients and in a rodent fibrosis model. Pulmonary fibrosis was evaluated in bleomycin (BLM)-induced lung injury in wild type and AhR knockout (Ahr-/- ) mice. The effects of IGF1R inhibition and AhR activation in vitro on TGF-ß1-induced epithelial-mesenchymal transition (EMT) in Beas2B cells and in vivo on BLM-exposed mice were also examined. KEYRESULTS:
There were increased IGF1R levels but AhR expression decreased in the lung of idiopathic pulmonary fibrosis patients and BLM-induced mice. Knockout of AhR aggravated lung fibrosis, while the use of IGF1R inhibitor and AhR agonist significantly attenuated such effects and inhibited TGF-ß1-induced epithelial-mesenchymal transition in Beas2B cells. Both TGF-ß1 and BLM markedly suppressed AhR expression through endoplasmic reticulum stress and consequently, IGF1R activation. The IGF1R inhibitor and specific knockdown of IGF1R reversed the activation of the TGF-ß1 signal pathway. CONCLUSION AND IMPLICATIONS In the development of idiopathic pulmonary fibrosis, AhR and IGF1R play opposite roles via the TGF-ß/Smad/STAT signalling cascade. The AhR/IGF1R axis is a potential target for the treatment of lung injury and fibrosis.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Receptor IGF Tipo 1
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Receptores de Hidrocarboneto Arílico
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Fibrose Pulmonar Idiopática
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Lesão Pulmonar
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article