A single injection of the long-acting CNP analog, MS~[Gln6,14]CNP-38, significantly reduced lung inflammation and fibrosis in a mouse model of pulmonary fibrosis.
Does C-type natriuretic peptide (CNP) or its long-acting analog reduce lung inflammation and fibrosis in preclinical models?
Endogenous CNP signaling in lung fibroblasts acts as a brake on inflammation and fibrosis, and pharmacological augmentation with long-acting CNP analogs represents a potential therapeutic strategy for pulmonary fibrosis.
Activation of lung fibroblasts in response to epithelial injury and inflammation provokes pulmonary fibrosis (PF). Endogenous molecular brakes counteracting fibroblast activity can be targets for therapies. Preclinical studies of synthetic C-type natriuretic peptide (CNP) indicated that this hormone might provide such a brake. As shown here, CNP exerts antifibrotic effects in cultured lung fibroblasts as well as precision cut lung slices from patients with PF, supporting clinical relevance. Therefore, augmenting or supplementing endogenous CNP could improve the treatment of such patients. To unravel whether paracrine CNP counteracts inflammation-driven PF, we studied mice with fibroblast-restricted knock-out of guanylyl-cyclase-B (GC-B), its cGMP-synthesizing receptor. Fibroblast GC-B-KO mice had enhanced bleomycin-induced lung inflammation, with increased expression of proinflammatory, profibrotic cytokines. Nevertheless, subsequent PF was not exacerbated. Molecular studies revealed that inflammation led to inhibition of CNP signaling in resident myofibroblasts, namely GC-B downregulation and induction of CNP/cGMP-degrading pathways. Despite this, a single subcutaneous injection of the recently developed long-acting CNP analog, MS~Gln6,14CNP-38, abrogated experimental lung inflammation and fibrosis. We conclude that CNP signaling in lung fibroblasts has anti-inflammatory and antifibrotic effects. Attenuation of this endogenous brake participates in the pathogenesis of PF and rescuing this pathway with long-acting CNP-analogs may have therapeutic potential.
Weyer et al. (2026) studied this question. A single injection of the long-acting CNP analog, MS~[Gln6,14]CNP-38, significantly reduced lung inflammation and fibrosis in a mouse model of pulmonary fibrosis.