# Pathophysiological and therapeutic implications of C-type natriuretic peptide/cyclic GMP signaling in pulmonary fibrosis

## TL;DR

This study explores how C-type natriuretic peptide (CNP) signaling in lung fibroblasts can reduce inflammation and fibrosis, suggesting potential new treatments for pulmonary fibrosis.

## Contribution

The study introduces a novel genetic mouse model and a long-acting CNP analog to investigate CNP/cGMP signaling in pulmonary fibrosis.

## Key findings

- CNP has antifibrotic effects in cultured lung fibroblasts and patient-derived lung slices.
- A long-acting CNP analog reduced experimental lung inflammation and fibrosis in mice.
- CNP signaling inhibition contributes to the pathogenesis of pulmonary fibrosis.

## Abstract

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 in 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 KO 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 s.c. injection of the recently developed long-acting CNP analog, MS~[Gln6,14]CNP-38, abrogated experimental lung inflammation and fibrosis. We conclude that CNP signaling in lung fibroblasts has antiinflammatory 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.

We used a novel genetic mouse model and a recently developed stabilized long acting CNP analog, to dissect the pathophysiological and therapeutic implications of CNP/cyclic GMP signaling in inflammation-driven pulmonary fibrosis<strong>. </strong>