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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic disease of the lung that is characterised by a progressive increase in fibrosis of the interstitial tissue (Raghu et al, 2011)
We previously reported that proliferation of human lung fibroblasts in response to platelet-derived growth factor (PDGF) is dependent on ERK1/2 phosphorylation, and that direct stimulation of adenylyl cyclase to increase cAMP could inhibit PDGF-dependent proliferation with no negative impact on cell viability (Roberts et al, 2018)
When we activated endogenous Gαs-coupled G protein-coupled receptors (GPCRs) in human lung fibroblasts, we found that the magnitude of the cAMP response was not predictive of the extent of the inhibitory effect on proliferation (Roberts et al, 2018)
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic disease of the lung that is characterised by a progressive increase in fibrosis of the interstitial tissue (Raghu et al, 2011). Areas of active alveolar epithelial cells and myofibroblasts co-localise in the lungs of patients with IPF to contribute to disease progression (Uhal et al, 1998). In IPF, fibroblasts differentiate into myofibroblasts that persist inappropriately in foci of the fibrotic lung. Accumulation of these myofibroblasts leads to excessive deposition of extracellular matrix, increased tissue stiffness, and scarring, all of which contribute to the progressive loss of lung function (Maher et al, 2007)
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