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Prostaglandin E2 and the pathogenesis of pulmonary fibrosis.

ABSTRACT: Prostaglandin (PG)E(2) is a bioactive eicosanoid that regulates many biologically important processes in part due to its ability to signal through four distinct G-protein-coupled receptors with differential signaling activity and unique expression patterns in different cell types. Although PGE(2) has been linked to malignancy in many organs, it is believed to play a beneficial role in the setting of fibrotic lung disease. This is in part due to the ability of PGE(2) to limit many of the pathobiologic features of lung fibroblasts and myofibroblasts, including the ability of PGE(2) to limit fibroblast proliferation, migration, collagen secretion, and, as originally reported in the Journal by us in 2003, the ability to limit transforming growth factor (TGF)-?-induced myofibroblast differentiation. In the setting of lung fibrosis, PGE(2) production and signaling is often diminished. In the last 8 years, significant advances have been made to better understand the dysregulation of PGE(2) production and signaling in the setting of lung fibrosis. We also have a clearer picture of how PGE(2) inhibits myofibroblast differentiation and the receptor signaling pathways that can influence fibroblast proliferation. This review highlights these recent advances and offers new insights into the potential ways that PGE(2) and its downstream signals can be regulated for therapeutic benefit in a disease that has no validated treatment options.

SUBMITTER: Bozyk PD

PROVIDER: S-EPMC3175580 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Prostaglandin E2 and the pathogenesis of pulmonary fibrosis.

Bozyk Paul D PD Moore Bethany B BB

American journal of respiratory cell and molecular biology 20110318 3

Prostaglandin (PG)E(2) is a bioactive eicosanoid that regulates many biologically important processes in part due to its ability to signal through four distinct G-protein-coupled receptors with differential signaling activity and unique expression patterns in different cell types. Although PGE(2) has been linked to malignancy in many organs, it is believed to play a beneficial role in the setting of fibrotic lung disease. This is in part due to the ability of PGE(2) to limit many of the pathobio ...[more]

PMID: 21421906

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Project description:Inflammatory responses in the peritoneum contribute to peritoneal dialysis (PD)-associated peritoneal fibrosis. Results of our previous study showed that increased microsomal prostaglandin E synthase-1-mediated production of prostaglandin E2 (PGE2) contributed to peritoneal fibrosis. However, the role of its downstream receptor in the progression of peritoneal fibrosis has not been established. Here, we examined the role of PGE2 receptor 4 (EP4) in the development of peritoneal fibrosis. EP4 was significantly upregulated in peritoneal tissues of PD patients with ultrafiltration failure, along with the presence of an enhanced inflammatory response. In vitro experiments showed that exposure to high glucose concentrations enhanced EP4 expression in rat peritoneal mesothelial cells (RPMCs). High-glucose-induced expression of inflammatory cytokines (monocyte chemoattractant protein-1, tumour necrosis factor α, and interleukin 1β) was significantly reduced in RPMCs treated with ONO-AE3-208, an EP4 receptor antagonist. ONO-AE3-208 also significantly decreased the expression of extracellular matrix proteins induced by high glucose concentrations. Furthermore, ONO-AE3-208 blunted activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and phosphorylation of nuclear factor kappa B (NF-κB) (p-p65). To further investigate the functional role of EP4, ONO-AE3-208 was administrated for 4 weeks in a rat model of PD, the results of which showed that ONO-AE3-208 inhibited peritoneal fibrosis and improved peritoneal dysfunction. Additionally, inflammatory cytokines in the peritoneum of PD rats treated with ONO-AE3-208 were downregulated, in line with inhibition of the NLRP3 inflammasome and NF-κB phosphorylation. In conclusion, an EP4 antagonist reduced the development of peritoneal fibrosis, possibly by suppressing NLRP3 inflammasome- and p-p65-mediated inflammatory responses. Our findings suggest that an EP4 antagonist may be therapeutically beneficial for PD-associated peritoneal fibrosis.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open.Main bodyOver the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities.ConclusionsBuilding on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

Project description:BackgroundDiabetic cardiomyopathy (DCM) is a cardiac complication of long-term uncontrolled diabetes and is characterized by myocardial fibrosis and abnormal cardiac function. Mesenchymal stem cells (MSCs) are multipotent cells with immunoregulatory and secretory functions in diabetes and heart diseases. However, very few studies have focused on the effect and the underlying mechanism of MSCs on myocardial fibrosis in DCM. Therefore, we aimed to explore the therapeutic potential of MSCs in myocardial fibrosis and its underlying mechanism in vivo and in vitro.MethodsA DCM rat model was induced using a high-fat diet (HFD) combined with a low-dose streptozotocin (STZ) injection. After four infusions of MSCs, rat serum and heart tissues were collected, and the levels of blood glucose and lipid, cardiac structure, and function, and the degree of myocardial fibrosis including the expression levels of pro-fibrotic factor and collagen were analyzed using biochemical methods, echocardiography, histopathology, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA). We infused prostaglandin E2 (PGE2)-deficient MSCs to DCM rats in vivo and established a system mimicking diabetic myocardial fibrosis in vitro by inducing cardiac fibroblasts with high glucose (HG) and coculturing them with MSCs or PGE2-deficient MSCs to further explore the underlying mechanism of amelioration of myocardial fibrosis by MSCs.ResultsMetabolic abnormalities, myocardial fibrosis, and cardiac dysfunction in DCM rats were significantly ameliorated after treatment with MSCs. Moreover, the levels of TGF-β, collagen I, collagen III, and collagen accumulation were markedly decreased after MSC infusion compared to those in DCM hearts. However, PGE2-deficient MSCs had decreased ability to alleviate cardiac fibrosis and dysfunction. In addition, in vitro study revealed that the concentration of PGE2 in the MSC group was enhanced, while the proliferation and collagen secretion of cardiac fibroblasts were reduced after MSC treatment. However, MSCs had little effect on alleviating fibrosis when the fibroblasts were pretreated with cyclooxygenase-2 (COX-2) inhibitors, which also inhibited PGE2 secretion. This phenomenon could be reversed by adding PGE2.ConclusionsOur results indicated that MSC infusion could ameliorate cardiac fibrosis and dysfunction in DCM rats. The underlying mechanisms might involve the function of PGE2 secreted by MSCs.

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Prostaglandin E2 and the pathogenesis of pulmonary fibrosis.

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Prostaglandin E2 and the pathogenesis of pulmonary fibrosis.

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