Dual inhibition of integrin alpha-v beta-6 (αvβ6) and integrin alpha-v beta-1 (αvβ1) showed an additive effect in reducing collagen expression in lung explant cultures from patients with idiopathic pulmonary fibrosis (IPF), according to a new study published in Respiratory Research.
“Using a well-characterized set of small-molecule and antibody-based integrin inhibitors, we evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced [transforming growth factor-β (TGF-β)] signaling and fibrogenic gene expression in human [precision-cut lung slices (PCLSs)],” the authors explained.
This effect was more potent than that observed when using clinically relevant concentrations of nintedanib (Ofev®) or pirfenidone (Esbriet®) in both fibrotic human and mouse lung slices.
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To achieve the dual inhibition of αvβ6/αvβ1, Decaris et al used PLN-74809, which is roughly equipotent for inhibition of both integrins (50% inhibitory concentration values, 5.7 nM and 3.4 nM, respectively) and is ≥ 445-fold selective over other αv integrins.
They were able to suppress about 2/3 of the activin receptor-like kinase 5 (ALK5)-driven collagen gene expression in lung explant cultures. ALK5 is a type I TGF-β receptor. Moreover, they observed a dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition in response to PLN-74809 treatment.
In addition, they found that after treating PCLSs for 7 days with PLN-74809, the αvβ6/αvβ1 inhibitor, Smad2 phosphorylation was reduced by nearly 50%. Since Smad2 is a canonical mediator of the TGF-β signaling, this observation was consistent with the inhibition of the downstream signaling cascade.
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“While other αv integrins have been implicated in TGF-β activation, additional experiments performed with mouse PCLSs showed no additional reduction in fibrogenic gene expression resulting from inhibiting additional αv integrins with GSK3008348 or CWHM-12 (ie, inhibition of αvβ3, αvβ5, and/or αvβ8 in addition to αvβ6 and αvβ1),” the authors clarified.
By adopting the dual αvβ6/αvβ1 inhibition strategy, the authors avoided the complete suppression of the TGF-β signaling, thereby reducing the likelihood of excessive toxicity.
Reference
Decaris ML, Schaub JR, Chen C, et al. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021;22(1):265. doi:10.1186/s12931-021-01863-0
