Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of isoliensinine (IL), a bisbenzylisoquinoline alkaloid extracted from the Chinese traditional medicine seed embryo of Nelumbo nucifera Gaertn., on bleomycin (BLM)-induced pulmonary fibrosis in mice were investigated. Seventy-two male Kungming mice were divided randomly into eight groups as BLM-IL10, BLM-IL20, BLM-IL40, BLM-Sal, Sal-IL10, Sal-IL20, Sal-IL40 and Sal-Sal groups. BLM (0.1 mg in 0.05 ml saline per animal, once) or saline (0.05 ml per animal, once) was applied intratracheally, and IL (10, 20, 40 mg/kg) or saline was administered orally 3 times per day in the appropriate groups. Animals were sacrificed 14 days after intratracheal treatment. Lung tissue and serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta 1 (TGF-beta (1)) were determined by biochemical measurements and immunohistochemistry. BLM treatment resulted in a significant increase of the hydroxyproline content and an obvious lung histological injury as compared to the Sal-Sal group. Administration of IL remarkably suppressed the increase in hydroxyproline content and abated the lung histological injury induced by BLM. There was a decrease in SOD activity and an increase in MDA level in lung tissue and serum in the BLM-Sal group (p < 0.01 , p < 0.01, vs. Sal-Sal group, respectively). And IL could obviously enhance the SOD activity and decrease the MDA level in a concentration-dependent manner. Moreover, IL also significantly inhibited the overexpression of TNF-alpha and TGF-beta (1) induced by BLM. These results indicated that IL possessed a significant inhibitory effect on BLM-induced pulmonary fibrosis, probably due to its antioxidant and/or anti-inflammatory activities and inhibitory overexpressing TNF-alpha and TGF-beta (1) induced by BLM.
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PMID:Inhibitory effects of isoliensinine on bleomycin-induced pulmonary fibrosis in mice. 1577 May 42

Based on current evidence, transforming growth factor (TGF)-beta plays a central pathogenic role in the development of pulmonary fibrosis. There is growing evidence that angiotensin II can serve as a stimulus for TGF-beta-mediated lung fibrosis. However, the role of angiotensin II in the pathobiology of pulmonary fibrosis in vivo remains unclear and the therapeutic potential for targeting angiotensin II in a bleomycin-induced pulmonary fibrosis model is not well known. Therefore, the aim of this study was to test whether the angiotensin II antagonist, losartan, attenuated the development of bleomycin-induced pulmonary fibrosis in two distinct murine strains, C57/BL6 and Sv129. This was determined by histopathology and quantification of collagen content by hydroxyproline assay. Despite demonstrable angiotensin II antagonism in vivo and a reduction in measures of acute lung injury, losartan therapy, at a dose shown to reduce renal and cardiac fibrosis in mice, failed to significantly ameliorate bleomycin-induced pulmonary fibrosis. In conclusion, these data suggest that the pulmonary fibrotic disease process in vivo is not solely dependent on angiotensin II activity and the potential for angiotensin II receptor blockers as a therapeutic strategy in patients with pulmonary fibrosis may be limited.
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PMID:Angiotensin II antagonism fails to ameliorate bleomycin-induced pulmonary fibrosis in mice. 1580 47

Transplant-related lung fibrosis is characterized by excessive fibro-collagenous deposition. Induction of arginase, an enzyme that metabolizes L-arginine to urea and L-ornithine, is vital for collagen synthesis. Pirfenidone is an investigational anti-fibrotic agent shown to be effective in blocking pulmonary fibrosis. The purpose of this study was to determine if pirfenidone was protective against the development of fibro-collagenous injury in rat lung orthotopic transplants through altering L-arginine-arginase metabolic pathways. Lung transplants were performed using Lewis donors and Sprague-Dawley recipients (allografts) or the same strain (isografts). Recipients were given pirfenidone (0.5% chow) 1-21-day post-transplantation. A significantly increased peak airway pressure (PawP) with excessive collagen deposition was found in untreated lung allografts. Pirfenidone treatment decreased PawP and collagen content in lung allografts. The beneficial effects were associated with downregulation of arginase protein expression and activity. In addition, pirfenidone decreased endogenous transforming growth factor (TGF)-beta level in lung allografts, and TGF-beta stimulated arginase activity in a dose-dependent manner in both lung tissue and fibroblasts. These results suggest that pirfenidone inhibits local arginase activity possibly through suppression of endogenous TGF-beta, hence, limiting the development of fibrosis in lung allografts.
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PMID:Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway. 1588 29

Transforming growth factor beta-1 is involved in local signaling for a variety of human diseases including renal diseases, cardiac hypertrophy and fibrosis in heart failure, hepatic fibrosis, and pulmonary fibrosis. Elevated levels of circulating transforming growth factor beta-1 result in organ fibrosis in animal models. In humans smoking, hypertension, diabetes and obesity appear to result in elevated circulating levels. This paper outlines a hypothesis that elevated circulating levels of transforming growth factor beta-1 are part of the molecular link between several entities that have epidemiologic ties including hypertension, diabetes, smoking and obesity on one hand and diseases resulting in organ fibrosis on the other including renal disease and cardiac fibrosis and hypertrophy in heart failure. Additionally, it is suggested that elevated levels are not simply a marker of a similar mechanism of disease production but that elevated levels of circulating transforming growth factor beta-1 lead to disease production and to the synergy of risk factors seen in production of human fibrotic diseases.
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PMID:Circulating transforming growth factor beta-1: a partial molecular explanation for associations between hypertension, diabetes, obesity, smoking and human disease involving fibrosis. 1612 68

Pulmonary fibroblasts regulate extracellular matrix production and degradation; thus, they are critical for maintenance of lung structure, function, and repair. In pulmonary fibrosis, fibroblasts produce excess collagen and form fibrotic foci that eventually impair lung function, but the mechanisms responsible for these alterations are not known. Receptors coupled to the stimulation of cAMP production can inhibit activation of fibroblasts and thereby are antifibrotic. To test whether this signaling pathway is altered in pulmonary fibrosis, we compared the ability of normal adult human pulmonary fibroblasts to generate and respond to cAMP with that of cells isolated from lungs with idiopathic pulmonary fibrosis. Serum- and transforming growth factor (TGF)-beta-stimulated cell proliferation was inhibited approximately 50% by forskolin and approximately 100% by prostaglandin (PG) E(2) in the normal cells but substantially less in the diseased cells. Collagen synthesis was also inhibited >50% by the same drugs in the normal cells but significantly less so in the diseased cells, despite responding with similar increases in cAMP production. Although expression of protein kinase A (PKA) and cAMP-stimulated PKA activity were similar in both the normal and diseased cell types, forskolin- and PGE(2)-stimulated cAMP response element-binding protein (CREB) phosphorylation was decreased in the diseased cell lines compared with the normal cells. cAMP-mediated activation and TGF-beta-mediated inhibition of CREB DNA binding was also diminished in the diseased cells. Thus, pulmonary fibroblasts derived from patients with pulmonary fibrosis are refractory to the inhibition by cAMP due to altered activity of components distal to the activity of PKA, in particular the phosphorylation of CREB.
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PMID:Fibrotic lung fibroblasts show blunted inhibition by cAMP due to deficient cAMP response element-binding protein phosphorylation. 1607

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase whose ligand is collagen. Recently, we have reported the association of DDR1 in the cytokine production of human leukocytes in in vitro and in vivo expression in idiopathic pulmonary fibrosis. However, its role in in vivo inflammation has not been fully elucidated. Small interference RNA (siRNA) can induce specific suppression of in vitro and in vivo gene expression. In this study, using a bleomycin-induced pulmonary fibrosis mouse model, we administered siRNA against DDR1 transnasally and evaluated histological changes, cytokine expression, and signaling molecule activation in the lungs. Histologically, siRNA against DDR1 successfully reduced in vivo DDR1 expression and attenuated bleomycin-induced infiltration of inflammatory cells. Furthermore, it significantly reduced inflammatory cell counts and concentrations of cytokines such as MCP-1, MIP-1alpha, and MIP-2 in bronchoalveolar lavage fluid. Subsequently, bleomycin-induced up-regulation of TGF-beta in bronchoalveolar lavage fluid was significantly inhibited, and collagen deposition in the lungs was reduced. Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs. Considered together, we propose that DDR1 contributes to the development of bleomycin-induced pulmonary inflammation and fibrosis.
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PMID:Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation. 1894 Dec 59

Idiopathic pulmonary fibrosis has a poor prognosis and few efficacious treatments. The immunosuppressant cyclosporin A has been shown to inhibit tumour growth factor (TGF)-beta-induced collagen deposition in vitro, and is widely used in Japan as a potent antifibrotic agent. Tacrolimus (FK506) is another attractive immunosuppressant, which may be useful in the treatment of pulmonary fibrosis. The aim of the present study was to elucidate the antifibrotic effect of FK506. The inhibitory effect of FK506 on collagen synthesis in cultured lung fibroblastic cells, TIG-3-20, and its antifibrotic effect on bleomycin (BLM)-induced pulmonary fibrosis in mice was investigated. FK506 inhibited TGF-beta-induced collagen synthesis, and suppressed the expression of TGF-beta type I receptor (TbetaR-I) in TIG-3-20 cells. Consistent with the in vitro findings, FK506 treatment starting on day 6 attenuated BLM-induced pulmonary fibrosis, in part, via reduced TbetaR-I expression. FK506 treatment in the acute BLM injury phase unexpectedly increased pro-inflammatory cytokine levels in bronchoalveolar lavage fluid and enhanced lung injury, resulting in poor survival. In conclusion, the present results suggest that FK506 has a potent antifibrotic effect and may be useful for the treatment of pulmonary fibrosis, although its use in the acute inflammatory phase may exacerbate lung injury.
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PMID:Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis. 1650 44

Fibrocytes are cells that circulate in the peripheral blood and produce connective tissue proteins such as vimentin and collagens I and III. Fibrocytes are associated with skin lesions, pulmonary fibrosis, and tumors and they contribute to the remodeling response by secreting matrix metalloproteinases. Fibrocytes can further differentiate, and they are a likely source of the contractile myofibroblast that appears in many fibrotic lesions. There is evidence in the skin for a prominent role for fibrocytes in the development of hypertrophic scars and keloids. In asthma or in experimental models of pulmonary fibrosis, fibrocytes have been shown to infiltrate areas of inflammation and tissue damage. Fibrocytes constitute part of the stromal response to tumor invasion, and there is evidence that these cells may be a prognosticator of malignant potential. IL-1, TGF-beta, chemokines, and serum amyloid P modulate the appearance and function of fibrocytes. Fibrocytes themselves produce inflammatory cytokines, growth factors, and chemokines. The intercellular signals that modulate fibrocyte trafficking, proliferation, and differentiation are only partially defined, but a better understanding of these signals enable new therapies to prevent pathologic fibrosis or to improve the tissue repair response.
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PMID:The role of circulating fibrocytes in fibrosis. 1656 74

TGF-Beta plays an important role in the genesis and progression of pulmonary fibrosis. We sought to determine the role of mononuclear phagocytes in the activation of TGF-beta and found that freshly isolated peripheral blood monocytes spontaneously released TGF-beta. Stimulating these monocytes with GM-CSF or LPS, but not MCSF, augmented the activation of TGF-beta. In human monocytes, the free thiol compounds DTT and NAC decreased the activity of TGF-beta, without affecting TGF-beta mRNA transcription. Both NAC and DTT lessened the biological activity of recombinant active TGF-beta in a cell-free system. We found that NAC and DTT reduced dimeric active TGF-beta from a 25 kDa protein to 12.5 kDa inactive monomer. This conversion was reversed using the oxidizing agent diamide. Diamide also restored biological activity to NAC or DTT-treated TGF-beta. Reduction of TGF-beta to monomers could competitively inhibit active dimeric TGF-beta and block intracellular signaling events. Our observations suggest that modulation of the oxidative state of TGF-beta may be a novel therapeutic approach for patients with pulmonary fibrosis.
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PMID:NAC and DTT promote TGF-beta1 monomer formation: demonstration of competitive binding. 1660 67

Uteroglobin (UG) is an anti-inflammatory protein secreted by the airway epithelia of all mammals. UG-knockout (UG-KO) mice sporadically develop focal pulmonary fibrosis (PF), a group of complex interstitial disorders of the lung that has high mortality and morbidity; however, the molecular mechanism(s) remains unclear. We report here that UG-KO mice are extraordinarily sensitive to bleomycin, an anti-cancer agent known to induce PF and readily develop PF when treated with an extremely low dose of bleomycin that has virtually no effect on the wild type littermates. We further demonstrate that UG prevents PF suppressing bleomycin-induced production of pro-inflammatory T-helper 2 cytokines and TGF-beta, which are also pro-fibrotic. Our results define a critical role of UG in preventing the development of PF and provide the proof of principle that recombinant UG may have therapeutic potential.
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PMID:Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. 1687 5


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