Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:009431 (fibronectin)
 32,104 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selected functions of alveolar macrophages obtained by bronchoalveolar lavage of 12 healthy smokers were examined before and after eight weeks' treatment with an inhaled glucocorticosteroid, budesonide (400 micrograms twice daily). After budesonide treatment spontaneous as well as opsonised zymosan triggered prostaglandin E2 (PGE2) secretion from harvested cells was reduced; no such reduction in opsonised zymosan triggered leukotriene B4 (LTB4) production was observed. Neither the capacity to phagocytose opsonised yeast particles nor the superoxide radical generation triggered by the calcium ionophore A23187, 4 beta-phorbol 12-myristate 13-acetate (PMA), or opsonised zymosan ex vivo were more than marginally affected by the glucocorticosteroid treatment in vivo. Lavage fluid concentrations of angiotensin converting enzyme (ACE), however, after treatment were twice those before treatment and concentrations of fibronectin were reduced to half. Albumin concentrations in lavage fluid were not affected by the glucocorticosteroid treatment. In separate experiments treatment of alveolar macrophages with 10(-7) or 10(-6) M budesonide overnight in vitro did not affect their superoxide radical or PGE2 generation but significantly blocked LTB4 release. These data indicate that inhaled gluco-corticosteroid treatment may affect synthesis or release (or both) of ACE and fibronectin by alveolar macrophages from healthy smokers whereas other functions of these cells, such as the generation of reactive oxygen derived products ex vivo, are only marginally affected.
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PMID:Effects of an inhaled corticosteroid, budesonide, on alveolar macrophage function in smokers. 216 59

Ataxia-telangiectasia and xeroderma pigmentosum are human hereditary diseases in which patients are cancer prone and demonstrate increased sensitivity to DNA damage by ionizing and ultraviolet radiation, respectively. In culture, both ataxia-telangiectasia and xeroderma pigmentosum skin fibroblasts show increased synthesis and secretion of the extracellular matrix proteins fibronectin and collagen. To determine whether these differences in protein production result from fundamental abnormalities in regulation of genes associated with cellular interactions, we compared the effects of trifluoperazine and 12-O-tetradecanoylphorbol-13-acetate on expression of the extracellular matrix-degrading metalloproteinases, procollagenase and prostromelysin, by normal, ataxia-telangiectasia, and xeroderma pigmentosum fibroblasts. After trifluoperazine treatment the overall levels of these metalloproteinases were much greater in three ataxia-telangiectasia cell strains and in cells from xeroderma pigmentosum complementation groups A and D than in normal cells. In contrast, cells from xeroderma pigmentosum complementation group C produced only slightly more procollagenase than normal cells. 12-O-tetradecanoylphorbol-13-acetate also induced higher than normal levels of procollagenase in some ataxia-telangiectasia and xeroderma pigmentosum strains, but less than that induced by trifluoperazine. Because increased extracellular accumulation of matrix-degrading enzymes has long been implicated in metastatic progression, this altered expression of procollagenase and prostromelysin in ataxia-telangiectasia and xeroderma pigmentosum cells could play an important role in the pathogenesis of various tumors in individuals with these genetic diseases.
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PMID:Enhanced expression of procollagenase in ataxia-telangiectasia and xeroderma pigmentosum fibroblasts. 217 6

Fibronectin (FN), a glycoprotein present in the plasma and the extracellular matrix, has been shown to enhance adherence-related functions of polymorphonuclear leukocytes (PMNs). In this study we investigated the effects of FN on the activation of human PMNs in suspension by soluble stimuli, as determined by the generation of superoxide radicals (respiratory burst). FN (up to 100 micrograms/ml) did not directly stimulate the PMN respiratory burst assessed using a sensitive assay, luminol-dependent chemiluminescence (CL). Low FN concentrations (Up to 25 micrograms/ml) caused a dose-dependent enhancement of the CL induced by two chemoattractants. N-formyl-methionyl-leucyl-phenylalanine (FMLP) and platelet-activating factor (Paf), and also by phorbol myristate acetate (PMA), a known protein kinase C activator. Higher FN concentrations were less effective. The potentiation involved both initial rate and total CL responses and was more active on extracellular than intracellular generation of oxygen radicals. FN potentiation persisted after cell washing and was abolished by treatment of FN with trypsin. Measurement of the respiratory burst using the cytochrome c reduction assay confirmed that FN enhanced both the initial rate and total amount of superoxide anion generated by FMLP-stimulated PMNs. These data indicate that FN facilitates the respiratory burst of chemoattractant-stimulated PMNs and suggest that FN can prepare PMNs in suspension for amplified biological functions induced by soluble inflammatory stimuli.
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PMID:Priming effect of fibronectin on respiratory burst of human neutrophils induced by formyl peptides and platelet-activating factor. 217 7

The lectin concanavalin A (ConA) causes fibroblasts to acquire an arborized morphology and to express elevated levels of collagenase. The temporal and mechanistic aspects of ConA regulation of matrix metalloproteinases (MMPs) and the tissue inhibitor of matrix metalloproteinases (TIMP) were characterized in early passage human fibroblasts. Collagenase (MMP-1), measured by functional assays in the absence of TIMP and also as immunoprecipitated [35S]methionine-labeled protein, was increased 10-20-fold following ConA (20 micrograms/ml, 2 x 10(-7) M) treatment for 24-72 h, with active collagenase comprising approximately 20% of the total collagenase activity. By comparison, MMP-2 (72-kDa gelatinase; molecular mass, 72 kDa, +dithiothreitol; 66 kDa, -dithiothreitol), analyzed by enzymography and following affinity purification, was increased less than 2-fold by ConA and was present entirely as an activated, 61-kDa (+dithiothreitol; 59 kDa, -dithiothreitol) form. Northern hybridization analyses revealed that ConA elevated the steady-state mRNA levels for MMPs; collagenase mRNA increased approximately 16-fold, MMP-2 increased 2-fold, and Pump-1, a recently described MMP gene, was induced. Concomitantly, a 10-fold reduction in TIMP protein and mRNA levels by ConA occurred. In comparison, 12-O-tetradecanoylphorbol-13-acetate (50 ng/ml, 8 x 10(-8) M), which also stimulates collagenase expression strongly (greater than 30-fold), elevated TIMP protein and mRNA levels (2- and 3-fold, respectively) and did not affect MMP-2 expression. The changes in MMP and TIMP mRNA levels induced by ConA were blocked by the protein synthesis inhibitor cycloheximide, and the half-lives of collagenase and MMP-2 mRNAs (53 and 46 h, respectively) were unaffected, indicating that ConA exerts its effects transcriptionally, through pathways requiring de novo protein synthesis. Increased transcription of the mmp genes was confirmed by nuclear run-on analyses; mmp-1 transcription was increased by greater than 25-fold, mmp-2 by approximately 3-fold, and Pump-1 by approximately 7-fold. In contrast, Timp gene transcription was reduced by approximately 80%, revealing reciprocal regulation of MMPs and TIMP during the induction of a resorptive cell phenotype. Decreased amounts of collagen and fibronectin, but not of SPARC (secreted protein, acidic and rich in cysteine) in the conditioned medium was the result of MMP activity since steady-state mRNA levels and transcription of the respective matrix protein genes were unaffected by ConA.
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PMID:Concanavalin A produces a matrix-degradative phenotype in human fibroblasts. Induction and endogenous activation of collagenase, 72-kDa gelatinase, and Pump-1 is accompanied by the suppression of the tissue inhibitor of matrix metalloproteinases. 217 35

Tubular cysts consisting of dilatation of the collecting ducts at the level of the subcapsular zone of the kidney were induced in newborn rabbits by a single injection of methylprednisolone acetate. We describe here the structural and compositional modifications of the tubular basement membrane (BM) during the formation, growth, and regression of the tubular cysts. During development of the tubular cysts the cystic BM appeared thickened and multilayered, with numerous matrix vesicles. Alcian blue- (AB) and ruthenium red- (RR) positive material distributed differently along the BM of control and cystic tubuli. While the amount of RR-positive material appeared increased in the cystic BM, no differences in the intensity of the AB staining could be discerned between normal and cystic tubuli. Immunofluorescent staining for laminin and type IV collagen appeared to be slightly decreased in the cystic tubuli. However, the amount of fibronectin appeared clearly increased. These changes in the cystic BM appear at the beginning of the tubular dilatation and are not observed in other renal BM. We suggest that there is a causal relationship between the modifications of the BM and the development of the tubular cysts. Glucocorticoids appear to modify the synthesis and/or secretion of the BM components. An abnormal BM should modify the spatial and chemical signals encoded within the BM that, in turn, could lead to abnormal behavior of the tubular cells. This may result in a loss of the normal developmental constraints imposed upon the tubular epithelium, which then undergoes cystic dilatation. During the regression of the cysts, the abnormalities of the BM progressively disappear. The sharp increase in the number of interstitial cells, which show close relationships with the components of the BM, suggests that these cells may be involved in the removal of the cyst BM.
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PMID:Basement membrane alterations during development and regression of tubular cysts. 218 34

The present study is a detailed kinetic analysis of the synthesis, release and multimerization of fibronectin (FN) in normal and tumor promoter-treated human lung fibroblasts. Pulse/chase and surface labeling experiments were performed to follow the fate of both newly synthesized and preexisting cell-surface FN over time. The majority of FN (80%) left the intracellular compartment within one hour of synthesis. However, the rate of direct secretion was very low and after one hour, 70% of newly synthesized FN was still at the cell surface. This material was primarily dimeric. Dimeric and multimeric (very high molecular weight) FN was detectable at the cell surface and in the medium 4 hours after synthesis. Pulse-labeled FN multimer levels peaked at 12 hours and declined thereafter. After 24 hours, 85% of pulse-labeled FN had been shed into the medium and the labeled FN remaining at the cell surface was primarily multimeric. Surface labeling experiments confirmed that the majority of FN resides at the cell surface prior to release into the medium. One hour treatment with the phorbol ester tumor promoter, 12-0-tetradecanoyl phorbol-13-acetate (TPA), stimulated a nine-fold increase in release of preexisting, dimeric cell-surface FN (125I-labeled). The major effect of longer term TPA treatment up to nine hours was continued depletion of dimeric cell-surface FN. Increased release of cell-surface multimeric FN was also stimulated by TPA, but to a much lesser extent. Release of newly synthesized (pulse-labeled) dimeric FN was also stimulated by TPA though much less than pre-existing FN, and TPA treatment produced a small decrease in the steady-state level of multimeric FN. Thus, preexisting cell-surface FN and newly synthesized FN differ dramatically in their susceptibility to TPA treatment.
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PMID:The kinetics of fibronectin synthesis and release in normal and tumor promoter-treated human lung fibroblasts. 223 5

A human macrophagelike cell line which grows in serum-free medium was established from a histiocytic lymphoma cell line, U-937. U-937 cells failed to differentiate into macrophagelike cells in serum-free medium plus 12-O-tetradecanoyl phorbol 13-acetate (TPA). Fibronectin and albumin in serum were necessary for differentiation of U-937 cells into macrophagelike cells in enriched RDF medium supplemented with insulin, transferrin, ethanolamine, selenite, egg yolk lipoprotein (eRDF-ITESL medium). The established cell line exhibited several characteristic properties of macrophage such as nitroblue tetrazolium reduction, phagocytic and alpha-naphthylbutyrate-esterase activities, and tumor necrosis factor and interleukin 1 production. At present the cells have been continuously maintained in eRDF-ITESL medium through over 150 passages.
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PMID:Establishment of a macrophagelike cell line derived from U-937, human histiocytic lymphoma, grown serum-free. 224 57

A metalloproteinase with Mr 29,000 was purified to homogeneity as a latent proenzyme from the conditioned medium of a human rectal carcinoma cell line CaR-1. This enzyme hydrolyzed casein more potently than gelatin embedded in polyacrylamide gels in zymography assay. Calcium ion was essential for the activity. It exerted the maximum activity at pH 7-9. Its activity was stimulated by organomercurials, such as p-amino-phenyl mercuric acetate and p-chloromercuric benzoic acid, and was inhibited by 1,10-phenanthroline but was hardly affected by diisopropyl fluorophosphate and pepstatin. When the purified proenzyme was activated by the organomercurials, it effectively hydrolyzed fibronectin, laminin, type IV basement membrane collagen, and several types of gelatins but not interstitial type I and III collagens. The treatment of the purified proenzyme with p-aminophenyl mercuric acetate or trypsin formed an active peptide with Mr 20,000. The structural analysis indicated that it was most likely identical to putative metalloproteinase-1, the complementary DNA of which had been cloned from human tumor mRNAs capable of hybridizing to a rat transin complementary DNA. Based on the fact that this enzyme is secreted extracellularly and degrades the matrix proteins, we propose the name "matrin" for this newly identified enzyme.
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PMID:Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line. 225 19

The interaction between granulocytes and endothelial walls may be influenced by the blood flow. This possibility was investigated by studying the influence of fluid flow on the adhesion and detachment of 51Cr-labeled rat granulocytes interacting with protein-coated glass surfaces. It is concluded that: i) Adhesion is markedly decreased when the wall shear rate becomes higher than about 20 s-1. ii) Pretreating glass with concanavalin A or polylysine significantly decreased adhesion, whereas fibronectin had little effect on binding. iii) Very high flow rates (about one thousandfold higher than those compatible with bond formation) were required to provoke substantial detachment of substrate-bound cells. iv) Coating glass with laminin or polylysine decreased binding strength whereas fibronectin or concanavalin A did not substantially influence this parameter. v) Exposing granulocytes to phorbol myristate acetate might increase the cell ability to form strong adhesions, whereas labile adhesion was unaffected or even decreased by this treatment.
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PMID:Mechanisms of leukocyte adhesion. 226 9

Human rheumatoid synovial cells in culture secrete at least three related metalloproteinases that digest extracellular matrix macromolecules. One of them, termed matrix metalloproteinase 2 (MMP-2), has been purified as an inactive zymogen (proMMP-2). The final product is homogeneous on SDS/PAGE with Mr = 72,000 under reducing conditions. The NH2-terminal sequence of proMMP-2 is Ala-Pro-Ser-Pro-Ile-Ile-Lys-Phe-Pro-Gly-Asp-Val-Ala-Pro-Lys-Thr, which is identical to that of the so-called '72-kDa type IV collagenase/gelatinase'. The zymogen can be rapidly activated by 4-aminophenylmercuric acetate to an active form of MMP-2 with Mr = 67,000, and the new NH2-terminal generated is Tyr-Asn-Phe-Phe-Pro-Arg-Lys-Pro-Lys-Trp-Asp-Lys-Asn-Gln-Ile. However, following 4-aminophenylmercuric acetate activation, MMP-2 is gradually inactivated by autolysis. Nine endopeptidases (trypsin, chymotrypsin, plasmin, plasma kallikrein, thrombin, neutrophil elastase, cathepsin G, matrix metalloproteinase 3, and thermolysin) were tested for their abilities to activate proMMP-2, but none had this ability. This contrasts with the proteolytic activation of proMMP-1 (procollagenase) and proMMP-3 (prostromelysin). The optimal activity of MMP-2 against azocoll is around pH 8.5, but about 50% of activity is retained at pH 6.5. Enzymic activity is inhibited by EDTA, 1,10-phenanthroline or tissue inhibitor of metalloproteinases, but not by inhibitors of serine, cysteine or aspartic proteinases. MMP-2 digests gelatin, fibronectin, laminin, and collagen type V, and to a lesser extent type IV collagen, cartilage proteoglycan and elastin. Comparative studies on digestion of collagen types IV and V by MMP-2 and MMP-3 (stromelysin) indicate that MMP-3 degrades type IV collagen more readily than MMP-2, while MMP-2 digests type V collagen effectively. Biosynthetic studies of MMPs using cultured human rheumatoid synovial fibroblasts indicated that the production of both proMMP-1 and proMMP-3 is negligible but it is greatly enhanced by the treatment with rabbit-macrophage-conditioned medium, whereas the synthesis of proMMP-2 is constitutively expressed by these cells and is not significantly affected by the treatment. This suggests that the physiological and/or pathological role of MMP-2 and its site of action may be different from those of MMP-1 and MMP-3.
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PMID:Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. 226 96


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