Bruton’s Tyrosine Kinase Could Be a Potential Therapeutic Target for PAH

Researchers from China showed that inhibition of Bruton’s tyrosine kinase (BTK) improved pulmonary arterial hypertension (PAH), pulmonary vascular remodeling, and right ventricle hypertrophy in a rodent model of PAH. Moreover, it alleviated pulmonary vascular fibrosis and decreased endothelial-to-mesenchymal transition (EndMT).

“These beneficial effects of BTK inhibition are associated with the suppression of [nucleotide-binding oligomerization domain-like receptor with pyrin domain 3] inflammasome and NF-κB/MAPK signaling, thereafter reduce M1 macrophage polarization and M1-related inflammatory cytokine production, and thereafter, alleviate EndMT and pulmonary vascular remodeling,” the researchers explained.

Yu et al used the compound BGB-3111 to selectively inhibit BTK. Intragastric administration of BGB-3111 suppressed monocrotaline (MCT)-induced increase of perivascular macrophages and recruitment of polarized M1 macrophages (inflammatory), but not M2 macrophages (immunosuppressive), to the bronchoalveolar lavage fluid. Changes in macrophage polarization phenotype (M1/M2) have been implicated in the development and progression of PAH.

Moreover, it counteracted MCT-induced upregulation of inducible nitric oxide synthase, arginase-1, and proinflammatory cytokines, such as interleukins 6 and 1β and the tumor necrosis factor α, in the lung. The effects of BGB-3111 were dose-dependent.

The results of the study, recently published in Oxidative Medicine and Cellular Longevity, also showed that monocrotaline (MCT)-induced PAH rats have increased expression of BTK in the lungs compared to animals in the control group. BTK expression was mostly restricted to macrophages, rather than smooth muscle cells or endothelial cells.

In vitro studies using U937 monocyte-derived macrophages and human pulmonary arterial endothelial cells corroborated in vivo findings. They further showed that BGB-3111 downregulated the phosphorylation of the signaling mediators, including the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, the NF-κB inhibitor IκBα, and the transcription factor p65.

BTK is a nonreceptor tyrosine kinase involved in the differentiation and activation of B lymphocytes.

Reference

Yu M, Wu X, Peng L, et al. Inhibition of Bruton’s tyrosine kinase alleviates monocrotaline-induced pulmonary arterial hypertension by modulating macrophage polarization. Oxid Med Cell Longev. Published online August 29, 2022. doi:10.1155/2022/6526036