Effects of the angiotensin II type 2 receptor agonist buloxibutid on human lung myofibroblasts and IPF lung tissue

<bold>Rationale:</bold> In a recent interim analysis of an open label phase 2a clinical trial, the selective orally available angiotensin II type 2 receptor (AT2R) agonist buloxibutid (C21) improved lung function in IPF patients over a 36-week period. The AT2R is highly expressed on alveolar epithelial cells type 2 (AEC2), which act as progenitor cells and are critical for surfactant production and maintaining alveolar function and structure. When damaged, the AEC2 release TGFβ1, which is considered an important driver of pulmonary fibrosis. Moreover, dysfunctional AEC2 can transition into myofibroblasts that produce excess collagen. <bold>Methods and Results:</bold> Anti-fibrotic effects of buloxibutid were studied in primary human myofibroblasts (MyoF) co-cultured with airway epithelial cells and stimulated with TGFβ1 and TNF (BioMAP, Fibrosis panel). x§Buloxibutid significantly and dose-dependently reduced α-smooth muscle actin and N-cadherin. This was not seen in a MyoF monoculture system, suggesting paracrine signaling between the two cell types. In precision cut human IPF lung slices, clinically relevant concentrations of buloxibutid dose-dependently reduced TGFβ1 protein and mRNA expression by up to 61% and 56%, respectively. Buloxibutid also reduced collagen type I alpha 1 in the supernatant by 45%. In addition, buloxibutid stimulated the release of surfactant protein B and C by 70% and 120%, respectively. <bold>Conclusions:</bold> In human tissues and cells relevant to IPF pathology, buloxibutid inhibited TGFβ1 expression and ECM-producing mesenchymal cells, and stimulated surfactant protein release. These findings are consistent with the observed clinical efficacy of buloxibutid in IPF.