Myofibroblast differentiation in idiopathic pulmonary fibrosis: epigenetic mechanisms and therapeutic targeting by cAMP

特发性肺纤维化(IPF)是一种进行性和破坏性的肺部疾病，其特征是肺内形成不可逆转的疤痕。在英国，IPF影响着超过8000人。它会导致呼吸困难，通常会在几年内导致死亡。尽管进行了大量研究，但疾病的原因尚不清楚，也没有有效的治疗方法来阻止或减缓疾病的进展。肌成纤维细胞(一种细胞类型)是导致瘢痕形成(纤维化)的主要细胞，可以由成纤维细胞和上皮细胞(另外两种细胞类型)转化为强大的促纤维化介质，称为转化生长因子β1(TGFbeta1)。在正常情况下，肌成纤维细胞的形成被一种名为前列腺素E2(PGE2)的有效抗纤维化介质抑制。然而，在肌成纤维细胞形成的过程中，细胞逐渐失去产生这种介质的能力，导致成纤维细胞过度生长和瘢痕形成。我们的初步研究表明，外源性PGE2和相关药物可以抑制并在一定程度上逆转TGFbeta1诱导的正常肺成纤维细胞和上皮细胞向肌成纤维细胞的转化，从而阻止过度的瘢痕形成，为IPF患者提供新的治疗方法。在本研究中，我们将利用正常肺成纤维细胞和上皮细胞，研究TGFbeta1诱导肌成纤维细胞转化的机制以及外源性PGE2和相关药物对转化的影响，并确定这些药物的分子作用机制。此外，我们还将使用IPF患者的肺组织和肺纤维化的小鼠模型来验证细胞研究的结果。我们相信，我们的研究结果将提高我们对IPF发病机制的理解，并为PGE2和相关药物作为潜在的新疗法在不久的将来造福IPF患者提供临床前证据。

Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating lung disorder characterised by irreversible scarring of the lung. IPF affects over 8,000 people in the UK. It causes disabling breathlessness, and often leads to death within a few years. The cause of the disease is unknown despite much research and there is no effective therapy to stop or slow the disease progression. Myofibroblasts (a cell type) are the major cells responsible for the scar formation (fibrosis) and can be transformed from fibroblasts and epithelial cells (two other cell types) by the potent pro-fibrotic mediator termed transforming growth factor beta1 (TGFbeta1). Under normal conditions, the formation of myofibroblasts is inhibited by a potent antifibrotic mediator termed prostaglandin E2 (PGE2). However, during the process of myofibroblast formation, the cells gradually lose the capability to produce this mediator, resulting in excessive fibroblast growth and scar formation. Our preliminary studies suggest that exogenously supplied PGE2 and related drugs can inhibit and, to some extent, reverse the TGFbeta1-induced transformation from normal lung fibroblasts and epithelial cells to myofibroblasts, thus could stop the excessive scar formation and be beneficial for patients with IPF as novel therapies. In the studies proposed here we will use normal lung fibroblasts and epithelial cells to study the mechanisms of TGFbeta1-induced transformation to myofibroblasts and the effect of exogenous PGE2 and related drugs on the transformation and to determine the molecular mechanisms of action of these drugs. In addition, we will also use lung tissues from patients with IPF and a mouse model of pulmonary fibrosis to confirm the findings with cell studies. We believe that the outcome of our studies will improve our understanding of the pathogenesis of IPF and provide preclinical evidence for PGE2 and related drugs as potential novel therapies to benefit IPF patients in the near future.