Staying in the flow: PDE4B inhibitor BI 1015550 improves features of vascular dysfunction in lung fibrosis in virtro and in vivo

Background: The role of vascular dysfunction in the pathogenesis of pulmonary fibrosis has only recently emerged as an important contributor to the progression of disease. Several aspects such as increased vascular permeability and coagulation, increased immune cell infiltration and loss of endothelial specialization have been discussed as pathological features in pulmonary fibrosis. The anti-inflammatory and anti-fibrotic potential of phosphodiesterase 4 (PDE4) inhibition for the pharmacological management of lung fibrosis is well established pre-clinically, but failed so far to translate to patients due to dose limiting nausea and vomiting which is likely associated to subtype PDE4D inhibition. BI 1015550 is a novel preferential PDE4B inhibitor with suggested improved tolerability in humans.

Aim: To investigate the activity and molecular mode of action of BI 1015550 in disease relevant 3D models of endothelial injury in vitro and validation of results in a therapeutic rat model of Bleomycin (Bleo)-induced lung fibrosis.

Methods: Human lung microvascular endothelial cells were cultured in microfluidic chips to form functional tubes. After inducing fibrotic changes by stimulation with an IPF-relevant cytokine cocktail, functional and molecular readouts were performed to analyze the effect of treatment with BI 1015550. Bleo-induced lung fibrosis in rats was treated with BI 1015550 (2.5mg/kg, b.i.d. from day 10 – 20) and lung tissue was analyzed by RNA-Seq (NGS).

Results: BI 1015550 improves barrier integrity of injured endothelium up to 41% by increasing VASP phosphorylation. Furthermore, BI 1015550 reduces immune cell infiltration into injured endothelium up to 63% by inhibition of VCAM-1 and E-Selectin. NGS data of a Bleo rat model confirmed the beneficial effect of therapeutic treatment with BI 1015550 on markers of vascular dysfunction in vivo.

Conclusions: BI 1015550 shows beneficial effects on several features of vascular dysfunction in vitro, which was confirmed in a therapeutic in vivo model of lung fibrosis. In the context of the existing pre-clinical and clinical data (phase I and II studies), BI 1015550 proves to be a promising candidate for treating patients with pulmonary fibrosis.

This poster was previously presented at American Thoracic Society 2024, 17–22 May, San Diego, USA, 2024

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Artikel online veröffentlicht:
18. März 2025