C-type natriuretic peptide - Guanylyl cyclase B effects in Pulmonary Fibrosis

Pulmonary fibrosis (PF) is a progressive restrictive lung disease driven by fibroblasts hyperactivation and increased interstitial collagen deposition. PF can be idiopathic (IPF) or secondary to severe inflammation. For instance, after SARS-CoV-2 pneumonia, more than a third of patients develop fibrotic abnormalities. Hence there is a tremendous need for a better understanding of the molecular pathways preventing PF to find novel tractable targets. Infusion of exogenous synthetic C-type natriuretic peptide (CNP) exerted antifibrotic effects in experimental PF. To elucidate the possible therapeutical relevance, here we studied CNP actions in cultured lung fibroblasts from patients with IPF. Additionally, to dissect possible protective paracrine roles of the endogenous hormone, we generated a novel genetic mouse model with conditional, fibroblast-restricted GC-B deletion for studies of bleomycin-induced inflammatory PF.

In vitro exogenous CNP, via cGMP, prevented the profibrotic, pro-proliferative and pro-migratory effects of growth factors such as TGF-b and PDGF-BB on fibroblasts cultured from human “healthy” lung specimens. Notably, such inhibitory CNP actions were fully preserved in fibroblasts from IPF patients. In vivo one week after bleomycin instillation, the fibroblast GC-B KO mice displayed significant increases in pulmonary plasma leakage and immune cell infiltration as well as augmented albumin and Galectin-3 levels in their BAL fluid in comparison to control littermates, indicating aggravated inflammation. Nevertheless, the extent of subsequent interstitial fibrosis and the decline of lung compliance were not different between the two genotypes.

Our current studies are directed to further elucidate the regulation and action of CNP in idiopathic versus inflammatory PF.