Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are two polypeptide mediators which are believed to play a role in the evolution of idiopathic pulmonary fibrosis (IPF). We have evaluated the effect of these two substances on the expression of receptors for collagen (cC1q-R) and globular (gC1q-R) domains of C1q and on type I collagen in human lung fibroblasts. Two fibroblast subpopulations differing in C1q receptor expression were obtained by culturing human lung explants in medium containing fresh human serum and heated plasma-derived serum and separating them based on C1q binding [Narayanan, Lurton and Raghu: Am J Resp Cell Mol Biol. 1998; 17:84]. The cells, referred to as HH and NL cells, respectively, were exposed to TGF-beta and TNF-alpha in serum-free conditions. The levels of mRNA were assessed by in situ hybridization and Northern analysis, and protein levels compared after SDS-polyacrylamide gel electrophoresis and Western blotting. NL cells exposed to TGF-beta and TNF-alpha contained 1.4 and 1.6 times as much cC1q-R mRNA, respectively, whereas in HH cells cC1q-R mRNA increased 2.0- and 2.4-fold. The gC1q-R mRNA levels increased to a lesser extent in both cells. These increases were not reflected in protein levels of CC1q-R and gC1q-R, which were similar to or less than controls. Both TGF-beta and TNF-alpha also increased procollagen [I] mRNA levels in both cells. Overall, TNF-alpha caused a greater increase and the degree of response by HH fibroblasts to both TGF-beta and TNF-alpha was higher than NL cells. These results indicated that TGF-beta and TNF-alpha upregulate the mRNA levels for cC1q-R and collagen and that they do not affect gC1q-R mRNA levels significantly. They also indicated different subsets of human lung fibroblasts respond differently to inflammatory mediators.
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PMID:Regulation of human lung fibroblast C1q-receptors by transforming growth factor-beta and tumor necrosis factor-alpha. 1018 9

Alveolar macrophages (AM) express gelatinase B, a member of the matrix metalloproteinase family involved in the degradation and remodeling of extracellular matrix components. We evaluated the expression of gelatinase B in the course of idiopathic pulmonary fibrosis (IPF) by studying alveolar macrophages in culture AM and bronchoalveolar lavage fluid from 12 untreated patients with IPF, 11 patients with IPF under treatment with steroid and immunosuppressive agents, and 10 control subjects. By using zymography and quantitative image analysis, latent gelatinase B, as well an 88-kD active form, were investigated in culture medium (24 h) of AMs and were found to be significantly increased (P < 0.01) in untreated patients exhibiting severe IPF when compared with control subjects (4.1 +/- 1.7 versus 0.3 +/- 0.2 10(5) arbitrary units [AU]/10(4) AM for the 92-kD form). Concomitant studies of gelatinase B levels associated with cultured AM extracts or freshly harvested AM showed similar results, both at the mRNA and protein levels, respectively. Immunocytochemical studies on freshly harvested AM demonstrated that the enzyme was located mainly at the cell, suggesting some involvement of gelatinase B in AM migration. In contrast, gelatinase B activity secreted by AM tended to be normal in patients with IPF under steroid and immunosuppressive treatment. Simultaneously, level of the gelatinase B activity in epithelial lining fluid was increased in untreated IPF patients, whereas it was normal in treated patients. These results suggest that AM of patients with IPF are primed for gelatinase B expression and that steroid and immunosuppressive treatment induces negative modulation of the gelatinase B overexpression. We conclude that gelatinase B may play a role in lung remodeling in IPF.
Am J Respir Cell Mol Biol 1999 May
PMID:Overexpression of alveolar macrophage gelatinase B (MMP-9) in patients with idiopathic pulmonary fibrosis: effects of steroid and immunosuppressive treatment. 1022 60

We have found reduced activity of tumor necrosis factor (TNF)-alpha accompanying resolving and fibrosing alveolitis induced in NMRI mice by mineral particles (MnO2 and SiO2, respectively), which is in apparent contradiction to the well-recognized proinflammatory and profibrotic activities of this cytokine. The objective of this study was to examine the mechanisms involved in this paradoxical response in NMRI mice. Although lung tissue messenger RNA (mRNA) levels for TNF-alpha were transiently (up to 15 d) and persistently (up to 120 d) upregulated in the resolving and fibrosing models, respectively, these changes were not accompanied by a parallel release of TNF-alpha protein, which was respectively transiently and persistently downregulated in bronchoalveolar lavage fluid and bronchoalveolar lavage cell cultures. The downregulation of the TNF-alpha protein was concurrent with the accumulation of recruited polymorphonuclear neutrophils (PMNs) in alveoli, and coculture experiments showed that PMN explanted from the lungs of mice treated with silica particles were able to downregulate the expression of TNF-alpha protein by naive alveolar macrophages. In addition, PMN depletion prevented the downregulation of TNF-alpha induced by silica, further establishing the role of PMNs in the downregulation of TNF-alpha. The possible degradation of TNF-alpha by proteolytic enzymes could be excluded. Marked increases in soluble p55 and p75 TNF receptors (sTNF-R), as well as in interleukin (IL)-10, paralleled the downregulation of TNF-alpha protein. The role of these mediators in the observed reduction of TNF-alpha activity was confirmed by immunoneutralizing the activity of p55 and p75 sTNF-R and by using IL-10-deficient animals. Because IL-10 also exerts profibrotic activity in addition to its antiinflammatory activity, the protracted overproduction of IL-10 observed in fibrosing alveolitis may help the understanding of why, in NMRI mice treated with silica particles, lung fibrosis develops in association with a downregulation of TNF-alpha.
Am J Respir Cell Mol Biol 1999 Jul
PMID:Soluble tumor necrosis factor (TNF) receptors p55 and p75 and interleukin-10 downregulate TNF-alpha activity during the lung response to silica particles in NMRI mice. 1038 2

Connective tissue growth factor is a recently described chemoattractant and fibroblast mitogen which, because of sequence homology and weak binding to insulin-like growth factor (IGF)-1, has been proposed as the eighth member of the IGF binding protein (IGFBP) superfamily, named IGFBP-related protein 2 (IGFBP-rP2). Previous studies have implicated IGFBP-rP2 in a number of heterogeneous fibrotic pathologies, including renal fibrosis, dermal scleroderma, and bleomycin-induced pulmonary fibrosis in mice. Because profibrogenic cytokines may be produced by inflammatory cells, we developed a multiplex competitive reverse transcription/polymerase chain reaction to quantify IGFBP-rP2 transcripts in bronchoalveolar lavage cells from healthy subjects and patients with idiopathic pulmonary fibrosis (IPF) and pulmonary sarcoidosis. IGFBP-rP2 messenger RNA expression was enhanced > 10-fold (P < 0.003) in patients with IPF; > 40-fold (P < 0.006) in stage I/II sarcoidosis patients, and > 90-fold (P < 0.005) in stage III/IV sarcoidosis patients by comparison with healthy nonsmoking control subjects. We suggest these increases are predominantly associated with lymphocyte- and neutrophil-driven IGFBP-rP2 production. These findings, together with previous reports implicating other IGFBPs in the pathogenesis of pulmonary fibrosis, suggest that the complex network of IGFBPs within the human lung is an important determinant of the outcome of the fibroproliferative response to injury.
Am J Respir Cell Mol Biol 1999 Dec
PMID:Enhanced insulin-like growth factor binding protein-related protein 2 (Connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. 1057 66

The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.
Am J Respir Cell Mol Biol 2000 Jul
PMID:Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. 1087 47

Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.
Am J Physiol Lung Cell Mol Physiol 2000 Sep
PMID:TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? 1095 32

Lymphocyte infiltrate is a hallmark of inflammatory responses. We have previously shown that de novo-induced endothelial sialyl Lewis x (sLex) expression guides lymphocytes in an L-selectin-dependent manner to sites of acute organ transplant rejections. In this research, we have analyzed five groups of chronic lung inflammations to determine the presence of properly glycosylated, i.e., sulfated, sLex-decorated, L-selectin ligands. Two anti-sLex (2F3 and HECA-452) and one anti-6- and/or 6'-sulfated and/or 6,6'-bisulfated (MECA-79) monoclonal antibodies (mAbs) were used. The control lung specimens did not express L-selectin ligands on endothelium. In contrast, the endothelial staining intensity and the number of positive peribronchial venules and capillaries with mAbs 2F3, HECA-452, and MECA-79 were significantly greater in bronchial biopsies from patients with asthma compared with normal specimens (P<0.003). However, no significant increase of peribronchial endothelial reactivity with these antibodies was observed in adult respiratory distress syndrome, chronic bronchitis, fibrosing alveolitis, and granulomatous inflammation compared with controls. These data suggest that sulfated sLex glycans, acting putatively as ligands for L-selectin, could be instrumental in lymphocyte extravasation into human peribronchial lung tissue during asthma, but not so important in several other inflammatory lung diseases.
Am J Respir Cell Mol Biol 2000 Oct
PMID:Endothelial sulfated sialyl Lewis x glycans, putative L-selectin ligands, are preferentially expressed in bronchial asthma but not in other chronic inflammatory lung diseases. 1101 14

It has been reported that transforming growth factor (TGF)-beta, which plays an integral role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), suppresses proliferation of alveolar epithelial cells in vitro. Although hyperplastic lesions of alveolar lining epithelial cells (ALECs) are characteristic pathologic features of IPF, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II (T beta RII) gene. To detect a deletion in the polyadenine tract in exon 3 of the T beta RII gene, cells were isolated by microdissection from lung sections of IPF patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 IPF patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low T beta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the T beta RII gene occurred in some lesions of hyperplastic ALECs in IPF, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of IPF.
Am J Respir Cell Mol Biol 2001 Apr
PMID:Microsatellite instability in transforming growth factor-beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis. 1130 32

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling (ISEL) and propidium iodide staining; percent of alpha-smooth muscle actin (alpha-SMA) positive cells by fluorescence-activated cell sorter; and alpha1-(I) collagen, transforming growth factor (TGF)-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from IPF and control lungs. Growth rate was significantly lower in IPF fibroblasts compared with controls (13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d). Conversely, a significantly higher percentage of apoptotic cells was observed in IPF-derived fibroblasts (ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008). alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in IPF samples (62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01). IPF fibroblasts were characterized by an increase in pro-alpha1-(I) collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from IPF exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.
Am J Respir Cell Mol Biol 2001 May
PMID:Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. 1135 Aug 29

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial pneumonia limited to the lung and characterized by a fibroproliferative response with only minor signs of inflammation, which almost always causes rapid fibrotic destruction of the lung. In this study, we investigated genomic instability in IPF, using microsatellite DNA analysis, aiming to detect any specific genetic alterations for this disease. We used 40 highly polymorphic microsatellite DNA markers, in multiplex PCR assays, to examine 52 sputum specimens from IPF patients versus correspondent venous blood. Loss of heterozygosity (LOH) was found in 20 (38.5%) patients in at least one locus. These alterations were found on markers previously associated with lung cancer located on 1p34.3, 3p21.32-p21.1, 5q32-q33.1, 9p21 and 17p13.1 where MYCL1, FHIT, SPARC, p16(Ink4) and TP53 genes have been mapped respectively. These data provide new insights into IPF pathogenesis and a new perspective for its correlation with lung cancer.
J Cell Mol Med
PMID:MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. 1216 6


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