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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary fibrosis is a progressive life-threatening disease for which no effective therapy exists. Myofibroblasts are one of the key effector cells in pulmonary fibrosis and are the primary source of extracellular matrix production. Drugs that inhibit the differentiation of fibroblasts to myofibroblasts have potential as antifibrotic therapies. Peroxisome proliferator-activated receptor (PPAR)-gamma is a transcription factor that upon ligation with PPARgamma agonists activates target genes containing PPAR response elements. PPARgamma agonists have anti-inflammatory activities and may have potential as antifibrotic agents. In this study, we examined the abilities of PPARgamma agonists to block two of the most important profibrotic activities of TGF-beta on pulmonary fibroblasts: myofibroblast differentiation and production of excess collagen. Both natural (15d-PGJ2) and synthetic (ciglitazone and rosiglitazone) PPARgamma agonists inhibited TGF-beta-driven myofibroblast differentiation, as determined by alpha-smooth muscle actin-specific immunocytochemistry and Western blot analysis. PPARgamma agonists also potently attenuated TGF-beta-driven type I collagen protein production. A dominant-negative PPARgamma partially reversed the inhibition of myofibroblast differentiation by 15d-PGJ2 and rosiglitazone, but the irreversible PPARgamma antagonist GW-9662 did not, suggesting that the antifibrotic effects of the PPARgamma agonists are mediated through both PPARgamma-dependent and independent mechanisms. Thus PPARgamma agonists have novel and potent antifibrotic effects in human lung fibroblasts and may have potential for therapy of fibrotic diseases in the lung and other tissues.
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PMID:PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. 1573 87

Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations in the content and composition of the lung extracellular matrix, and we believe this "altered" matrix has the ability to promote lung carcinoma cell growth. One extracellular matrix molecule shown to be altered in these lung diseases is fibronectin (Fn). We previously reported increased growth and survival of non-small cell lung carcinoma (NSCLC) cells exposed to Fn. Thus Fn may serve as a mitogen/survival factor for NSCLC and therefore represents a novel target for anti-cancer strategies. To this end, we studied the effects of the PPARgamma ligands 15d-PGJ(2), rosiglitazone (BRL49653), and troglitazone on Fn expression in NSCLC cells and found that they were able to inhibit Fn gene transcription. Inhibition of Fn expression by BRL49653 and troglitazone, but not by 15d-PGJ(2), was prevented by the specific PPARgamma antagonist GW-9662 and by PPARgamma small interfering RNA. Working with Fn deletion and mutated promoter constructs, we found that the region between -170 and -50 bp downstream from the transcriptional start site of the promoter was involved in PPARgamma ligand inhibition. PPARgamma ligands also diminished the phosphorylation of CREB, diminished Sp1 nuclear protein expression, and prevented the binding of these transcription factors to CRE and Sp1 sites, respectively, within the Fn promoter. In summary, our results demonstrate that PPARgamma ligands inhibit Fn gene expression in NSCLC cells through PPARgamma-dependent and -independent pathways that affect both CREB and Sp1.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1. 1590 79

Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
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PMID:The Role of PPARs in Lung Fibrosis. 1771 Feb 35

Interest in peroxisome proliferator-activated receptors (PPARs) has steadily increased over the past 15 years. The recognition that subclasses of this receptor played critical roles in regulation of metabolism led to the development of synthetic ligands and their widespread application in the treatment of type 2 diabetes. At the same time, emerging evidence demonstrated that the influence of PPARs extends well beyond metabolism and diabetes. A salient example of this can be seen in studies that explore the role of PPARs in lung cell biology. In fact, current literature suggests that PPAR receptors may well represent exciting new targets for treatment in a variety of lung disorders. In an attempt to keep the scientific and medical communities abreast of these developments, a symposium sponsored by the American Federation for Medical Research entitled "PPARgamma: A Novel Molecular Target in Lung Disease" was convened on April 29, 2007, at the Experimental Biology Meeting in Washington, DC. During that symposium, 4 speakers reviewed the latest developments in basic and translational research as they relate to specific lung diseases. Jesse Roman, MD, professor and director of the Emory University Division of Pulmonary, Allergy, and Critical Care Medicine, reviewed the role of PPARgamma in the pathogenesis of lung cancer and its implications for therapy. Raju Reddy, MD, assistant professor of Medicine at the University of Michigan, presented data regarding the immunomodulatory role of PPARgamma in alveolar macrophages. Patricia J. Sime, MD, associate professor of Medicine, Environmental Medicine, and Oncology at the University of Rochester School of Medicine, discussed the antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. Finally, C. Michael Hart, MD, professor of Medicine at Emory University and chief of the Atlanta Veterans Affairs Medical Center Pulmonary Section, reviewed the role of PPARgamma in pulmonary vascular disease. This brief introduction to the symposium will provide background information about PPARs to facilitate the general reader's appreciation of the more in-depth and disease-specific discussions that follow.
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PMID:PPARgamma: a novel molecular target in lung disease. 1831 33

Pulmonary fibrosis is characterized by the accumulation of fibroblasts, myofibroblasts, collagen, and other extracellular matrix proteins in the interstitium of the lung, with subsequent scarring and destruction of the alveolar capillary interface. In some cases, pulmonary fibrosis is preceded by lung inflammation and can be treated with anti-inflammatory therapies. However, idiopathic pulmonary fibrosis is characterized by a relative paucity of underlying inflammation and currently has no effective treatment. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in controlling cell differentiation and that PPARgamma ligands can modify inflammatory and fibrotic responses. Peroxisome proliferator-activated receptor gamma ligands, including the thiazolidinedione class of antidiabetic drugs and novel triterpenoid compounds derived from oleanic acid, inhibit TGF-beta-stimulated profibrotic differentiation of lung fibroblasts in vitro and reduce lung scarring in animal models of fibrosis. The mechanism of action of the PPARgamma ligands is under investigation but seems to involve both PPARgamma-dependent and PPARgamma-independent pathways. These in vitro and in vivo data highlight the potentially exciting role of PPARgamma ligands as novel therapies for fibrosis of the lung and other organ systems prone to scarring. Many of the synthetic PPARgamma ligands are orally active, and several are currently available and Food Drug Administration approved for use in therapy of type 2 diabetes. Further research is urgently required to more clearly elucidate the mechanism of action of these drugs and to develop more potent antifibrotic agents for patients with scarring diseases for whom there are currently few effective therapies.
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PMID:The antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis. 1831 37

Inflammatory diseases of the lung such as asthma and COPD represent a major worldwide health problem. There are potent antiinflammatory drugs available to treat asthma, such as the glucocorticoids, but these produce unwanted side effects and exhibit limited efficacy in the treatment of COPD. The identification of the peroxisome proliferator-activated receptors (PPARs) PPARgamma, PPARalpha, and PPARdelta opened up a new avenue of research as it was discovered that they exhibited antiinflammatory and immunomodulatory properties. In animal models of allergic and occupational asthma, COPD and pulmonary fibrosis PPARs are involved in the inflammatory cascade, and treatment with PPAR agonists reduces inflammation and results in beneficial outcomes. The actions of PPARgamma and PPARalpha activation are thought to be due to their ability to down-regulate proinflammatory gene expression and inflammatory cell functions, and as such makes them an attractive target for novel drug intervention. PPARdelta has been shown to be involved in wound healing, and its activation may enhance the effects of PPARgamma agonists. The only fly in the ointment is the observation of an increased incidence of cardiovascular events in diabetic patients treated with the PPARgamma agonist rosiglitazone. However, a clinical trial is underway to examine the effect of rosiglitazone in asthma patients, and the outcome of this trial is awaited with much anticipation. PPARs are novel targets for lung disease, and the continued work with PPAR agonists may result in a potential new treatment for these chronic inflammatory lung diseases.
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PMID:Peroxisome proliferator-activated receptors as novel targets in lung disease. 1862 17

Pulmonary fibrosis is a progressive scarring disease with no effective treatment. Transforming growth factor (TGF)-beta is up-regulated in fibrotic diseases, where it stimulates differentiation of fibroblasts to myofibroblasts and production of excess extracellular matrix. Peroxisome proliferator-activated receptor (PPAR) gamma is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that a novel PPARgamma ligand, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), is a potent inhibitor of TGF-beta-stimulated differentiation of human lung fibroblasts to myofibroblasts, and suppresses up-regulation of alpha-smooth muscle actin, fibronectin, collagen, and the novel myofibroblast marker, calponin. The inhibitory concentration causing a 50% decrease in aSMA for CDDO was 20-fold lower than the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15 d-PGJ(2)), and 400-fold lower than the synthetic ligand, rosiglitazone. Pharmacologic and genetic approaches were used to demonstrate that CDDO mediates its activity via a PPARgamma-independent pathway. CDDO and 15 d-PGJ(2) contain an alpha/beta unsaturated ketone, which acts as an electrophilic center that can form covalent bonds with cellular proteins. Prostaglandin A(1) and diphenyl diselenide, both strong electrophiles, also inhibit myofibroblast differentiation, but a structural analog of 15 d-PGJ(2) lacking the electrophilic center is much less potent. CDDO does not alter TGF-beta-induced Smad or AP-1 signaling, but does inhibit acetylation of CREB binding protein/p300, a critical coactivator in the transcriptional regulation of TGF-beta-responsive genes. Overall, these data indicate that certain PPARgamma ligands, and other small molecules with electrophilic centers, are potent inhibitors of critical TGF-beta-mediated profibrogenic activities through pathways independent of PPARgamma. As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high.
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PMID:Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts. 1928 77

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARgamma regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of genes involved in lipid biosynthesis and glucose metabolism. However, more recently PPARgamma, PPARalpha and PPARbeta/delta agonists have been demonstrated to exhibit anti-inflammatory and immunomodulatory properties thus opening up new avenues for research. The actions of PPARgamma and PPARalpha activation are thought to be due to their ability to down regulate pro-inflammatory gene expression and inflammatory cell functions, and as such makes them an attractive target for novel drug intervention. Interestingly, PPARbeta/delta has been shown to be involved in wound healing, angiogenesis, lipid metabolism and thrombosis. In this review we will focus on the data describing the beneficial effects of these ligands in the airway and in the pulmonary vasculature and in vivo in animal models of allergic and occupational asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. A clinical trial is underway to examine the effect of rosiglitazone in asthma patients and the outcome of this trial is awaited with much anticipation. In conclusion, PPARs are novel targets for lung disease and continued work with these ligands may result in a potential new treatment for chronic inflammatory lung diseases.
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PMID:Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease. 1970 65

Recent studies have indicated that peroxisome proliferator-activated receptor gamma (PPARgamma) is capable of modulating inflammation, which prompted us to investigate the potential of PPARgamma ligands as lung protective agents in pulmonary fibrosis. The present study was undertaken to investigate the effects of rosiglitazone (RSG), a highly potent ligand of PPARgamma, on migration, proliferation, and phenotypic differentiation of human lung fibroblasts (MRC-5) and to explore its potential for therapy of pulmonary fibrosis. The cell migration potential was observed in a scratch wound model. Cell proliferation was determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method, immunocytochemical staining, and flow cytometry, and protein expression by Western blot analysis. RSG slowed cell migration distance induced by fetal bovine serum (FBS), decreased cell proliferation initiated by FBS or platelet-derived growth factor-BB (PDGF-BB), and decreased alpha-smooth muscle actin (alpha-SMA) protein expression induced by transforming growth factor-beta1 (TGF-beta1). In addition, RSG incubation reduced the ratio of phospho-extracellular signal-regulated kinases 1/2 (p-ERK1/2) to ERK1/2 expression stimulated by FBS, PDGF-BB, and TGF-beta1. These findings show that RSG treatment inhibits lung fibroblast migration and proliferation and myofibroblast transdifferentiation stimulated by FBS and growth factors in vitro, which suggests that PPARgamma agonists could antagonize pulmonary fibrosis and have potential for therapeutic application in pulmonary fibrosis.
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PMID:Rosiglitazone inhibits migration, proliferation, and phenotypic differentiation in cultured human lung fibroblasts. 2020 97

AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis. Recent studies demonstrated that AMPK is a novel signaling molecule modulating inflammatory responses and oxidative stress which are involved in inflammatory pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary infectious diseases and pulmonary fibrosis. AMPK attenuates inflammatory lung injury by phosphorylating its downstream targets, such as sirtuin1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), p53 and forkhead box O3a (FoxO3a). This review summarized the relationship between AMPK and the development of inflammatory pulmonary diseases.
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PMID:[Recent advances in the study of AMPK and inflammatory pulmonary disease]. 2532 48


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