Inhibition of the Proliferation of Human Lung Fibroblasts by Prostacyclin Receptor Agonists is Linked to a Sustained cAMP Signal in the Nucleus

Abstract

Idiopathic pulmonary fibrosis is a chronic and progressive fibrotic lung disease, and current treatments are limited by their side effects. Proliferation of human lung fibroblasts in the pulmonary interstitial tissue is a hallmark of this disease and is driven by prolonged ERK signalling in the nucleus in response to growth factors such as platelet-derived growth factor (PDGF). Agents that increase cAMP have been suggested as alternative therapies, as this second messenger can inhibit the ERK cascade. We previously examined a panel of eight Gαs-cAMP-coupled G protein-coupled receptors (GPCRs) endogenously expressed in human lung fibroblasts. Although the cAMP response was important for the anti-fibrotic effects of GPCR agonists, the magnitude of the acute cAMP response was not predictive of anti-fibrotic efficacy. Here we examined the reason for this apparent disconnect by stimulating the Gαs-coupled prostacyclin receptor and measuring downstream signalling at a sub-cellular level. MRE-269 and treprostinil caused sustained cAMP signalling in the nucleus and complete inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. In contrast, iloprost caused a transient increase in nuclear cAMP, there was no effect of iloprost on PDGF-induced ERK in the nucleus, and this agonist was much less effective at reversing PDGF-induced proliferation. This suggests that sustained elevation of cAMP in the nucleus is necessary for efficient inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. This is an important first step towards understanding of the signalling events that drive GPCR inhibition of fibrosis.

Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

“…Lung fibrosis originates from aberrant repair of the lung epithelial cells and repeated injury [ 8 ]. Some studies hold the view that the progressive pulmonary dysfunction declining resulted from the lung epithelial injury as well as aberrant fibroblast proliferation participated in the development of inflammation and lung fibrosis [ 9 , 10 ]. Additionally, EMT and excessive extracellular matrix (ECM) production also result in pulmonary structural remodeling [ 11 , 12 ].…”

Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation

“…This temporal bias might convey informational content if cells are able to discriminate cAMP production from different sources and trigger unique biological outcomes differentially associated with these two phases. In this context, a sustained cAMP elevation was reported to be specifically required in several physiological responses, such as chronic inflammation and pain [34][35][36][37] , to resume meiosis in the oocyte 38 , and several reports indicate its role in cAMP-dependent nuclear transcription 30,31,[39][40][41][42][43] . Similarly, internalization-mediated sustained cAMP elevation can aid in producing stable responses to pulsatile or low-concentration hormones such as PTH.…”

Mangostanin Derivatives as Novel and Orally Active Phosphodiesterase 4 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis with Improved Safety

“…The second messenger cyclic adenosine monophosphate (cAMP) was reported to inhibit fibroblast proliferation or differentiation into myofibroblasts during the development of IPF. − Phosphodiesterase 4 (PDE4), the major cAMP-degrading enzyme in lung fibroblasts, is upregulated in the progression of fibrosis, and the selective PDE4 inhibitor, roflumilast, has in vivo and in vitro antifibrotic effects in IPF models. − In addition, PDE4 is widely involved in inflammatory processes, which are also active in the pathogenesis of IPF. , These evidences suggest PDE4 as a potential and attractive drug target for the treatment of IPF. However, the clinical use of PDE4 inhibitors is commonly limited by dose-dependent side effects such as emesis and nausea. ,, Thus, discovering novel PDE4 inhibitors with improved safety is challenging for the treatment of IPF.…”