Phosphodiesterase 2 is up-regulated in activated lung fibroblasts: impact on C-type natriuretic peptide/cGMP signalling and role in lung fibrosis

• Applicants: Swati Dabral, Ph.D.; Professorin Dr. Michaela Kuhn
• Subject Area: Anatomy and Physiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557205516

The prevalence of idiopathic pulmonary fibrosis (IPF) and profibrotic interstitial lung diseases is on the rise with more than 50,000 new cases diagnosed annually. Excessive extracellular matrix (ECM) deposition and destruction of the lung architecture diminishes lung compliance and leads to progressive respiratory insufficiency. The pathogenesis involves recurrent or prolonged inflammation that triggers fibroblast transition to myofibroblasts with enhanced proliferation, migration, and ECM production. IPF is currently treated with the tyrosine kinase inhibitors pirfenidone and nintedanib, which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. Hence, there is a tremendous need for a better understanding of the molecular pathways driving or preventing PF as basis for finding novel tractable targets. Our recent studies reveal that the endothelial hormone C-type natriuretic peptide (CNP), via its guanylyl cyclase (GC)-B receptor and cGMP signalling, inhibits the profibrotic activation of cultured human lung fibroblasts from patients with IPF. However, in lung myofibroblasts (in vitro and in situ) under inflammatory conditions, the molecular pathways mediating and regulating such antifibrotic CNP effects are impaired: the expression of the GC-B receptor is diminished, while the expression of the cGMP/cAMP degrading phosphodiesterase (PDE) 2 is markedly increased. Moreover, inflammation triggers increased fibroblast expression of the NP receptor C (NPR-C), which mediates the internalization and degradation (clearance) of CNP. Such “molecular remodelling” of activated lung fibroblasts, with loss of an antifibrotic endothelial-fibroblast communication, may contribute to the progression of PF. Conversely, rescuing this pathway and thereby restoring the antifibrotic effects of endogenously formed or exogenously administered CNP might prevent or delay this disease. If we can prove these hypotheses, then the involved molecules could be targets for novel therapies of PF. Therefore, here we propose studies in cultured or freshly isolated human and murine lung fibroblasts, precision cut murine lung slices as well as lung sections from patients with IPF to characterize the mechanisms driving augmented NPR-C and PDE2A expression, the impact on the antifibrotic effects of the CNP/GC-B/cGMP pathway, and the possible role in a “profibrotic” negative cGMP-to-cAMP crosstalk. To dissect the pathophysiological relevance, we will study whether a fibroblast-targeted genetic inhibition of NPR-C or PDE2 in mice attenuates the development of PF. Lastly, to evaluate the possible therapeutic implications, we will test whether administration of a recently developed long-acting form of CNP exerts anti-inflammatory and antifibrotic effects in experimental PF and whether such protective effects are enhanced by inhibiting NPR-C and/or PDE2.

• DFG Programme: Research Grants