Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present the first direct biochemical evidence for the turnover of intact type VI collagen microfibrils. Matrix-degrading enzymes of the serine proteinase class, including rat mast cell chymases I and II, human mast cell tryptase, neutrophil elastase, cathepsin G and trypsin, were able to catabolize intact type VI collagen microfibrils isolated from foetal bovine skin and metabolically labelled intact type VI collagen immunoprecipitated from fibroblast culture medium. By contrast, intact type VI collagen was not degraded by the human matrix metalloproteinases, MMP-1, MMP-2, MMP-3 and MMP-9. These data have important implications for the stability of type VI collagen in connective tissues and highlight the potential role of serine proteinases both in normal type VI collagen turnover and in inflammatory conditions characterized by matrix degradation.
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PMID:Catabolism of intact type VI collagen microfibrils: susceptibility to degradation by serine proteinases. 846

Results of studies of the epidemiology, physiology, histopathology, and cell biology of asthma have revised our conception of the disease. Epidemiologic studies have shown asthma to be an important cause of death, suffering, and economic hardship. Physiologic studies have shown that asthma is a chronic illness characterized by persistent bronchial hyperreactivity. Histopathologic studies have shown characteristic changes: epithelial damage, deposition of collagen beneath the basement membrane, eosinophilic and lymphocytic infiltration, and hypertrophy and hyperplasia of goblet cells, submucosal glands, and airway smooth muscle. Studies of the functions of cells in the airway mucosa suggest that asthma may be fundamentally mediated by a difference in the type of lymphocyte predominating in the airway mucosa but may also involve complex interactions among resident and migratory cells. Asthma may thus result from sensitization of a subpopulation of CD4+ lymphocytes, the Th2 subtype, in the airways. These lymphocytes produce a family of cytokines that favor IgE production and the growth and activation of mast cells and eosinophils, arming the airways with the mechanisms of response to subsequent reexposure to the allergen. This conceptual model has stimulated research along lines that will almost certainly lead to powerful new treatments, and it has already put current therapies in a new light, clarifying the role of antinflammatory agents, especially of inhaled corticosteroids. This conceptual model has some limitations: it ignores new evidence on the role of the mast cell in producing cytokines and depends on results of studies of the effects of inhalation of allergen, although most asthma exacerbations are provoked by viral respiratory infection. Preliminary studies suggest that viral infection and allergen inhalation may involve the activation of different pathways, with viral infection activating production of cytokines by airway epithelial cells. Similar study of the mechanisms activated by inhalation of air toxics may provide important clues as to how they might induce or exacerbate asthma.
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PMID:Basic mechanisms of asthma. 854 78

Bleomycin induces local inflammatory process with subsequent pulmonary fibrosis. An unknown chemoattractant induces the mast cell (MC) migration to the injured lung tissue. Aim of this study was evaluation of the number, topography and ultrastructure (TEM) of the MC in rat lungs with bleomycin-induced fibrosis. The bleomycin was administered once intratracheally (3.6 mg/kg). The animals were sacrificed on 7th. 14th and 21st day of experiment. MC were stained with Csaba's method. An evident increase in MC number related to the phase of experiment and stage of lung fibrosis was observed: 520, 1200, 4745 per cm2 section on the 7th, 14th and 21st day respectively. In control the MC number was 163 per cm2 section (p < 0.001). On the 7th day the MC were rich in red granules (mature granules with preponderance of heparin). They were located mainly in pleura and around the blood vessels, as in control. On the 14th and 21st day the majority of MC was situated in places of active fibrosing. They contained exclusively blue granules (the young granules with preponderance of biogenic amines), mixture of increased secretory function of the MC in the fibrotic lungs. Some of the MC granules showed fusion and altered matrix contents, other were emptied in piecemeal manner. A net of microtubules connected the granules was observed. Degranulation of MC may release heparin and cytokines able to stimulate synthesis of extracellular matrix. It has been suggested that heparin contributes to the fibrotic process and angiogenesis, stimulating directly or indirectly collagen synthesis by binding, stabilization and activation of fibroblast growth factor (FGF) and cell adhesion glycoproteins.
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PMID:[Morphology of mast cells in experimental pulmonary fibrosis induced with bleomysin]. 864 Jan 54

Interactions of cells with their extracellular matrix (ECM) are central to tissue-specific migration, localization, and function of migratory cells. Since mast cells circulate as immature precursor cells and home to tissues in a characteristic distribution, with increases in various disease states, we used the immature human mast cell line HMC-1 as a model to investigate the poorly understood mast cell-ECM interactions in humans. Functional adhesion studies showed that HMC-1 cells spontaneously adhere to fibronectin and laminin (80% at 6 and 12 microgram/ml, respectively) and to collagen type I and III (50% at 20 microgram/ml), whereas binding to vitronectin and collagen type IV required cell activation by phorbol myristate acetate. HMC-1 cells did not adhere to hyaluronic acid. Moreover, both fibronectin and laminin supported pronounced cytoplasmatic spreading with formation of isolated lamellipodia, whereas these cells exhibited a round cell shape on collagen and vitronectin, as shown by scanning electron microscopy. On flow cytometric analysis, HMC-1 cells expressed several adhesion molecules including the integrins beta 1, alpha 2 through alpha 6, alpha v, and alpha v beta 5, as well as CD44. Adhesion to fibronectin and vitronectin was found to be divalent cation- and arginine-glycine-aspartic acid-dependent, and could be blocked by antibodies to beta 1 or alpha 5, and alpha v or alpha v beta 5, respectively. In contrast, binding to laminin and collagen could not be blocked by monoclonal antibodies to any of the cell surface adhesion receptors expressed. Our results show that immature mast cells are able to modify their adhesive behavior in response to various ECM proteins and activating stimuli, and that this phenomenon is partly integrin mediated. These findings may be important for our understanding of the mechanisms leading to tissue-specific localization of mast cells.
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PMID:Interactions of immature human mast cells with extracellular matrix: expression of specific adhesion receptors and their role in cell binding to matrix proteins. 864 90

Mast cells have been shown to play a role in many chronic inflammatory and fibrotic disorders. However, their possible contribution to the pathological changes that occur in liver cirrhosis is unknown. To explore this, we examined whether changes in hepatic mast cell number and mediator content were associated with fibrotic changes in experimental biliary cirrhosis. Rats were studied 7, 14, or 21 days after bile duct resection (BDR). Hepatic mast cells were identified by histochemical and immunohistochemical stains. Rat mast cell protease II (RMCP-II), a marker of mast cell degranulation, was measured in liver by enzyme-linked immunosorbent assay. Hepatic collagen deposition was assessed by Sirius Red F3BA staining. In day 21 BDR rats, there was a one- to twofold increase (P < .001) in the number of hepatic mast cells, but this was not observed in day 7 or 14 BDR rats. Mild fibrotic changes were noted in BDR rat livers as early as 7 days after induction of cholestasis. Significant expansion and organization of fibrous tissue had occurred in day 14 BDR rats which progressed to bridging fibrosis by day 21. Liver RMCP-II levels were decreased by 50 percent (P < .05) and mast cell degranulation was apparent as shown by histamine immunostaining. These results suggest that hepatic mast cell hyperplasia and degranulation occur during prolonged cholestasis in the rat. Although these changes do not correlate with the onset of hepatic fibrosis, they do occur at a time during which there is significant deposition and organization extracellular matrix elements. Hepatic mast cells, by releasing profibrogenic mediators, may contribute to fibrotic changes in biliary cirrhosis.
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PMID:Hepatic mucosal mast cell hyperplasia in rats with secondary biliary cirrhosis. 866 46

Renal injury in diabetes mellitus is associated with progressive interstitial fibrosis and extracellular matrix accumulation. However, the phenotypes of cells forming the interstitial infiltrate in diabetic nephropathy have not been precisely defined. There is increasing evidence for the association of mast cells with angiogenesis, chronic inflammatory conditions and fibrosis. We have recently shown that human mast cells can produce the non-fibrillar short chain type VIII collagen in vivo. Using immunohistochemistry, in situ hybridisation and reverse transcriptase-polymerase chain reaction, we examined the contribution of mast cells and type VIII collagen to the fibrotic changes occurring in biopsy-proven diabetic nephropathy. We observed that the number of interstitial mast cells was significantly increased in diabetic nephropathy compared with normal kidney tissue. In specimens from diabetic subjects, intense immunohistochemical staining for type VIII collagen was detected in mast cells, on periglomerular fibres and in perivascular and interstitial sites. The expression of type VIII collagen in periglomerular and interstitial sites coincided with that of alpha smooth muscle actin, a marker for myofibroblastic differentiation mRNA for type VIII collagen was detected by reverse transcriptase-polymerase chain reaction in diabetic nephropathy and in a human mast cell line. By in situ hybridisation the transcripts for type VIII collagen were localised to renal mast cells. The increased number of mast cells and the elevated type VIII collagen deposition in human diabetic nephropathy provides a potential link between the extracellular matrix accumulation and the fibrosis observed in this condition.
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PMID:Mast cells and type VIII collagen in human diabetic nephropathy. 889 10

The development of mast cells from bone marrow precursors and their function as the mucosal- or connective-tissue-type mast cell are critically dependent on microenvironmental factors. Extracellular matrix proteins, such as collagen, fibronectin, and laminin, may represent insoluble components of the microenvironment. Recent studies have described multiple isoforms of laminin isolated from different tissues. In the present study, adhesion of mouse bone marrow-derived mast cells (BMMC) and long-term mast cell lines to Engelbreth-Holm-Swarm (EHS) tumor laminin, rat laminin, human merosin, and human placental laminin was compared. The greatest level of adhesion was found with human laminin as the substrate. By use of a newly prepared mouse VLA-alpha 6 integrin-specific mAb (MA6) together with the previously described mAb GoH3, VLA-6 (alpha 6 beta 1) integrin was found to be expressed and utilized by BMMC and long-term mast cell lines. VLA-6 has been described as a major laminin receptor with roles in diverse cell functions including cell growth and differentiation. BMMC have been shown to express a 32/67-kDa laminin receptor. Therefore, in addition to the 32/67-kDa laminin receptor described in early studies, BMMC also express VLA-6 integrin, which may have roles in the regulation of their development.
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PMID:Integrin VLA-6 (alpha 6 beta 1) mediates adhesion of mouse bone marrow-derived mast cells to laminin. 889 18

The effect of human mast cells on fibroblast activity was studied using an organotypic skin-equivalent culture system. Human mast cell-1 (HMC-1) cells were embedded in a collagen gel with neonatal dermal fibroblasts at a ratio of 1:4; keratinocytes then were allowed to stratify above this composite culture. Analysis of type a1(I) procollagen mRNA synthesis by in situ hybridization revealed a substantial increase in mRNA levels in the presence of mast cells and especially following degranulation, induced by calcium ionophore A23187. Tryptase, a major product of human mast cells, could substitute for mast cells in this culture system, up-regulating procollagen mRNA synthesis. Tryptase pretreated with the specific protease inhibitor bis(5-amidino-2-benzimidazo-lyl)methane (BABIM) markedly attenuated the collagen mRNA up-regulation. Further studies revealed HMC-1 cell sonicates stimulated fibroblast chemotaxis and procollagen mRNA synthesis. Inhibition of HMC-1 sonicates with either BABIM or a neutralizing mAb against tryptase resulted in significant reduction of fibroblast chemotaxis and procollagen mRNA, implying that tryptase accounted for the majority of HMC-1 sonicate activity. Tryptase directly stimulated fibroblast chemotaxis with optimal concentrations between 10 pM and 1 nM. The maximal response of optimal concentrations of tryptase was comparable with the known fibrogenic factor, TGF-beta. Inhibition of tryptase with BABIM resulted in approximately 50% reduction in chemotactic activity. Additional studies revealed that tryptase (0.3-3 nM) stimulated procollagen mRNA synthesis in confluent monolayers of dermal fibroblasts.
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PMID:Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis. 903 79

We recently demonstrated that cultured malignant schwannoma (MS)-derived cells can support human skin mast cell (HSMC) survival in vitro. Cultured HSMCs were spindleshaped in close contract with MS-derived cells, suggesting cell to cell interaction. To elucidate the mechanism of the enhanced HSMC survival in coculture with MS-derived cells and the cellular interactions between HSMC and MS-derived cells, we examined the immunocytochemical characteristics of MS-derived cells using immunofluorescence. Morphologically, cultured MS-derived cells were polygonal with abundant cytoplasm and resembled perineurial cells. The cultured cells immunoreacted positively with vimentin, fibronectin, laminin and collagen IV, but negatively with anti-S100 protein, anti-neuron specific enolase, and anti-neurofilament (68 kd, 145 kd, 200 kd) antibodies. MS-derived cells were distinct from Schwann cells in their lack of S100 protein and also distinguishable from endoneurial fibroblasts that produce fibronectin, but never expressed laminin or collagen IV. MS-derived cells thus possess the characteristics of perineurial cells in their general morphology and their immunocytochemical properties. Immunoreactivity for substance P (SP) and neurokinin A (NKA) was found in the cytoplasm of these cells, particularly around the nuclei. Vasoactive intestinal peptide, somatostatin, and calcitonin gene related peptide were negative. From these findings, we characterized the MS-derived cell's in vitro properties and concluded that it is similar to a perineurial cell. The extracellular matrix protein, laminin, and fibronectin expressed in the MS-derived cell might contribute to HSMC survival and morphology through cell to matrix adhesion. Neuropeptides such as SP and NKA, expressed in the MS-derived cell, might play some role in enhanced HSMC survival in vitro.
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PMID:Immunocytochemical characterization of malignant schwannoma-derived cells in culture. 904 33

Stem cell factor (SCF) has a major role in hematopoiesis and in the regulation of mast cell development and function. For example, recombinant human SCF (rhSCF) can induce the development of human mast cells from precursor cells in vitro, stimulate mediator release from human skin mast cells in vitro, and promote both the development and functional activation of human skin mast cells in vivo. In the present study, we used a new ultrastructural enzyme-affinity method, employing diamine oxidase (DAO)-conjugated gold particles (DAO-gold), to detect histamine in skin biopsies obtained from patients with breast carcinomas who were receiving daily subcutaneous (SC) injections of rhSCF in a phase I study of this cytokine. We examined control biopsies obtained at sites remote from rhSCF injection as well as biopsies of rhSCF-injected skin that were obtained within 2 hours and 30 minutes of the SC injection of rhSCF at that site. The rhSCF-injected sites (which clinically exhibited a wheal-and-flare response), but not the control sites, contained mast cells undergoing regulated secretion by granule extrusion. The DAO-gold-affinity method detected histamine in electron-dense granules of mast cells in control and injected skin biopsies; however, the altered matrix of membrane-free, extruded mast cell granules was largely unreactive with DAO-gold. Notably, DAO-gold bound strongly to fibrin deposits and collagen fibers that were adjacent to degranulated mast cells. These findings represent the first morphologic evidence of histamine secretion by classical granule exocytosis in human mast cells in vivo.
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PMID:Diamine oxidase-gold ultrastructural localization of histamine in human skin biopsies containing mast cells stimulated to degranulate in vivo by exposure to recombinant human stem cell factor. 937 68


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