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)

Peptides that modulate mesenchymal cell function have been detected in the fibrotic lung disorders once physiologic dysfunction is present. Despite this close association with manifest disease, their role in initiating alveolar remodeling remains unknown. We examined the hypothesis that one potent peptide, platelet-derived growth factor (PDGF), would be present at the alveolar surface before the onset of physiologic dysfunction in patients in whom pulmonary fibrosis subsequently develops. Bronchoalveolar lavage and physiologic assessment were performed in asymptomatic patients with the Hermansky-Pudlak syndrome (n = 30), obligate heterozygous (n = 9), and normal volunteers (control group). Lavage cell number and profile were normal, but alveolar macrophages demonstrated characteristic autofluorescence and ultrastructural features of ceroid. Lavage fluid from physiologically normal patients with Hermansky-Pudlak syndrome and from those with occult restrictive disease demonstrated two PDGF-related peptides (14 kd and 38 kd). Radioligand binding and fibroblast proliferation assay demonstrated that the peptides were functional. By immunoassay the concentration of PDGF in lavage fluid was six times greater than control values (p < 0.01). In situ hybridization together with bioassay indicated that alveolar macrophages were one cellular source of PDGF. Similar results were obtained for heterozygotes. These data identify macrophage-derived PDGF peptides as important candidate molecules in the initiation of alveolar remodeling in the fibrotic lung disorders.
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PMID:Pathogenesis of pulmonary fibrosis: platelet-derived growth factor precedes structural alterations in the Hermansky-Pudlak syndrome. 814 11

Lung fibrosis has been postulated to be mediated by the production of macrophage-derived growth factors that are both mitogenic and chemotactic for fibroblasts. In vitro studies from our laboratory demonstrated that alveolar and interstitial macrophages treated with iron and asbestos release platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) into the media. This conditioned media was capable of inducing proliferation and chemotaxis of primary rat lung fibroblasts (RLF). TGF-beta is known to be present in the media, and RLF have high-affinity receptors for TGF-beta. However, we found that > 95% of the chemotaxis was blocked by a polyclonal anti-PDGF antibody, whereas anti-TGF-beta did not change cell migration. TGF-beta has been described previously as a potent chemoattractant for fibroblasts. Thus, we tested the potential of purified TGF-beta to induce RLF chemotaxis in an attempt to address this apparent contradiction in results. Four separate preparations of RLFs from four different rats, Swiss 3T3 cells, human and rat fetal skin fibroblasts, and human foreskin fibroblasts were tested for chemotaxis using purified porcine TGF-beta 1 as well as human TGF-beta. None of these cells responded chemotactically to TGF-beta over a broad range of concentrations used (0.004 pg/ml to 50 ng/ml). RLF plated at different densities also did not respond to TGF-beta. On the other hand, all the fibroblast types migrated vigorously to PDGF (4 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early-passage rat lung fibroblasts do not migrate in vitro to transforming growth factor-beta. 848 Dec 30

Fibrosis in the lung directly underlying the field of irradiation is an almost universal long term sequelae of thoracic irradiation. It is assumed to represent the consequence of direct damage to local tissues and/or vascular endothelium by ionizing radiation. This view, however, is not in keeping with our current understanding of fibrotic processes, which suggest that growth factors for fibroblasts (including platelet-derived growth factor (PDGF), insulin-like growth factor I (IGF-I)) and cytokines stimulating collagen synthesis (notably transforming growth factor-beta) are largely responsible for this process. Since a major source of these factors is the macrophage, present in large numbers within the lung, it appeared possible that radiation-induced fibrosis might be mediated by similar mechanisms. Therefore, a study was designed to determine, first, whether in vitro irradiation of mononuclear phagocytes could induce the release of growth factors for fibroblasts. Second, we wished to ascertain whether these same growth factors might also be secreted by bronchoalveolar cells from humans who had undergone in vivo thoracic irradiation. The results of this study indicate that irradiation of a number of different types of mononuclear phagocytes resulted in the dose-dependent synthesis and release of several growth factors for fibroblasts, including PDGF, tumour factor-alpha (TNF-alpha) and IGF-I. Further, cells obtained by bronchoalveolar lavage from patients undergoing thoracic radiation spontaneously released PDGF following irradiation. These findings strongly support the contention that synthesis and release of macrophage-derived growth factors for fibroblasts (particularly PDGF and IGF-I) occur after thoracic irradiation and play a significant role in the pathogenesis of irradiation-induced pulmonary fibrosis in humans.
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PMID:Both in vitro and in vivo irradiation are associated with induction of macrophage-derived fibroblast growth factors. 856 89

Current concepts suggest that macrophages may play a central role in pulmonary fibrosis by virtue of their ability to release a variety of cytokines. In this study, the expression of interleukin (IL)-1 alpha and beta, platelet-derived growth factor (PDGF) A and B, and insulin-like growth factor (IGF) I in BAL cells, which may be involved in fibroblast proliferation, was investigated in murine bleomycin (BLM)-induced pulmonary fibrosis. BAL cells were obtained at 1, 15, and 29 days from Institute for Cancer Research mice after 10 days of intraperitoneal administration of BLM. The relative amounts of cytokine messenger RNA (mRNA) were evaluated by the reverse transcription-polymerase chain reaction method, which simultaneously amplified complementary DNA for cytokines and beta-actin as an internal control. The level of IL-1 beta mRNA in BLM-treated mice was increased 4.5-fold compared with that in saline solution-treated (control) mice 1 day after treatment, while no significant differences were observed between the two groups at 15 and 29 days. The mRNAs of PDGF-A and IGF-I in BLM-treated mice were sustained at levels eightfold and threefold to fourfold, respectively, those of controls over 4 weeks. No significant differences were noted in IL-1 alpha and PDGF-B expression between the two groups. We conclude that IL-1 beta released from macrophages may be important in the early phase of inflammatory responses and that PDGF-A and IGF-I may play important roles in the development of BLM-induced pulmonary fibrosis.
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PMID:Increased expression of platelet-derived growth factor A and insulin-like growth factor-I in BAL cells during the development of bleomycin-induced pulmonary fibrosis in mice. 861 91

The roles played by platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta) in the development of pulmonary fibrosis in equine chronic pneumonia varied greatly. Macrophages, epithelial cells and fibroblasts were identified as a source of PDGF, the principal role of which was related to its mitotic effect on epithelial cells, and particularly on fibroblasts in the final phase of the disease. TGF beta was detected in epithelial cells in all three phases of the disease and in fibroblasts in the last phase. However, the role of TGF beta in this pulmonary disease is not clear because its expression in the cytoplasm of fibroblasts in areas of strong collagenation during the last phase was weak. Nonetheless, it was responsible for the production and release of collagen during the stage of total fibrosis.
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PMID:Immunocytochemical detection of growth factors (PDGF and TGF beta) in equine chronic pneumonia. 874 62

Although the pathological patterns of interstitial pneumonia associated with collagen vascular disease (CVD-IP) resemble those of usual interstitial pneumonia in idiopathic interstitial pneumonia (IIP), the clinical features of CVD-IP and IIIP are quite different. We evaluated the differences between these conditions, with regard to the expression of genes in cells obtained by bronchoalveolar lavage. The reverse transcription-polymerase chain reaction was used to measure the levels of mRNA for IL-1 beta, TNF-alpha, IL-8, TGF-beta, PDGF-B, and IGF-1, and no significant differences were found between patients with CVD-IP and those with IIP. However, differential display analysis revealed a fragment that can be considered to have been derived from an unknown gene mRNA, and this was found only in patients with pulmonary fibrosis associated with progressive systemic sclerosis. Expression of specific genes may differentiate CVD-IP from IIP.
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PMID:[Pulmonary manifestation of collagen vascular diseases: role of cytokines in interstitial pneumonia associated with collagen vascular diseases]. 875 19

To elucidate the relevance of transforming growth factor (TGF)-beta 1 and platelet-derived growth factor (PDGF)-B to the pathogenesis of pulmonary fibrosis, we introduced each of these expression vectors via trachea into Wistar rat to overexpress them locally in the lungs by hemagglutinating virus of Japan (HVJ)-liposome method. The TGF-beta 1 gene induced significant proliferatin of fibroblasts and deposition of collagen fibrils with mild cellular infiltration. The PDGF-B gene induced mild fibrotic changes with some cellular infiltration. These findings suggest that both factors may be very closely relevant to the pathogenesis of lung fibrosis.
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PMID:[Role of TGF-beta and PDGF on the pathogenesis of pulmonary fibrosis--analysis by in vivo gene transfer]. 883 90

In the past several years, significant progress in many aspects of pulmonary fibrosis research has been made. Among them, the finding that a variety of cytokines play important roles in the complex process appears most intriguing. These cytokines include at least transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), platelet-derived growth factor, fibroblast growth factors, (TGF-alpha), interleukin-1, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha. These cytokines have been demonstrated to be produced at the sites of active fibrosis where they appear to be expressed by activated inflammatory cells, such as macrophages and eosinophils. More interestingly, other noninflammatory lung cells including mesenchymal cells, such as myofibroblasts, and epithelial cells, have been found to be significant sources as well, albeit in most instances at somewhat different time points than those by inflammatory cells. Study of the individual cytokines in vitro has revealed a variety of potential roles for these cytokines in the regulation of the fibrotic process in vivo, including chemoattractant, mitogenic activities for fibroblasts, stimulation of extracellular matrix and alpha-smooth muscle actin gene expression, alteration of the contractile phenotype of fibroblasts and regulation of diverse functions of lung inflammatory and epithelial cells which can further impact on the fibrotic process by autocrine and paracrine mechanisms. Of these cytokines, it appears that TGF-beta is probably the most important cytokine in terms of the direct stimulation of lung matrix expression which typifies fibrosis. Recently however, there is accumulating evidence to indicate that the situation is much more complex than any one single cytokine being solely responsible for the fibrotic response. The concept of complex lung cytokine networks, orchestrated by a few key cytokines, such as TNF-alpha, being responsible for this response has received strong support from recent studies. This means that it is the balance of positive (profibrogenic) and negative (antifibrogenic) forces generated from interaction among the various cytokines constituting these networks, which may finally determine the outcome of lung injury and inflammation. The importance of these cytokines also suggests new potential targets for designing new therapies for progressive pulmonary fibrosis, and perhaps their utility in prognostication as well.
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PMID:Cytokines and pulmonary fibrosis. 889 Nov 99

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.
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PMID:Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. 895 72

Neutrophils play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To elucidate the possible involvement of neutrophil elastase (NE) in pulmonary fibrosis, we investigated the efficacy of a new specific NE inhibitor (ONO-5046 Na) in a murine model of human IPF, bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage (BAL) and histopathological analysis were performed on bleomycin-treated mice (group A), bleomycin and ONO-5046 Na-treated mice (group B), and saline control groups at 1, 15, and 29 d after the end of bleomycin treatment. At 29 d, multifocal fibrosis was observed in group A, whereas no fibrotic regions were observed in group B. Interleukin-1 beta and macrophage inflammatory protein-2 mRNA levels in BAL cells on day 1, and platelet-derived growth factor-A and insulin-like growth factor-1 mRNA levels on days 1 and 15, were significantly lower in group B than in group A. Thus, we demonstrated an inhibitory effect of ONO-5046. Na on pulmonary fibrosis in mice, indicating the involvement of NE in the pathogenesis of pulmonary fibrosis. We propose that this effect might be related to suppressed expression of particular cytokines in alveolar macrophages and that this specific NE inhibitor could be a novel therapeutic agent for IPF.
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PMID:Effects of neutrophil elastase inhibitor on bleomycin-induced pulmonary fibrosis in mice. 923 Jul 58


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