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)

Human leukocyte elastase (HLE) has been demonstrated on lung elastic fibers in areas of pulmonary emphysema. In vitro studies in our laboratory have shown that HLE-elastin complexes may be remarkably stable. We tested the possibility that elastin-bound HLE may retain catalytic activity in the presence of inhibitors that are effective against free HLE and found: (1) alpha-1-proteinase inhibitor (alpha 1PI), antileukoprotease (ALP), and eglin C inhibited free HLE on an approximately 1:1 molar basis, measured with either 3H-elastin or a synthetic peptide substrate; (2) the ability of each inhibitor to control catalytic activity of HLE when complexed with elastin was impaired (e.g., in a 24-h assay, a 70-fold molar excess of alpha 1PI gave only 93% inhibition of HLE); and (3) a chloromethyl ketone inhibitor of HLE gave qualitatively similar results, although at the low enzyme concentrations used it was a less effective inhibitor of free and elastin-bound enzyme than were the polypeptide inhibitors. Further, we found evidence for two distinct mechanisms of inhibition of elastin-bound HLE. alpha 1PI and eglin C prevented elastin solubilization largely by enhancing net dissociation of HLE from the complexes; enzyme remaining bound to the substrate retained essentially full activity. In contrast, ALP and the chloromethyl ketone prevented elastin solubilization by binding to the complexes and inhibiting the enzyme in situ. These results may have implications regarding progressive elastin solubilization in vivo and should stimulate further investigation of enzyme activity in heterogeneous systems in which one or more reactants are insoluble.
Am J Respir Cell Mol Biol 1990 Mar
PMID:Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity. 231 May 84

Immunization of rabbits with elastin peptides prepared from purified bovine ligamentum nuchae elastin produces calcified arteriosclerotic lesions and fragmentation of elastic lamellae. Simultaneous administration of porcine calcitonin largely prevents the development of lesions. Experiments were carried out to clarify the mechanisms involved in the development of lesions as well as those involved in the preventive effect of calcitonin. Control experiments were carried out using bovine serum albumin (BSA) as antigen. Circulating antibodies and soluble immune complexes increased steadily in the sera of animals immunized with elastin peptides or BSA. The cellular immune reaction was weak as assessed by [3H]thymidine incorporation into lymphocytes in the presence of antigen or phytohemagglutinin. Arterial lesions appeared only in the animals immunized with elastin peptides, not in those immunized with BSA. Ion flux measurements were also carried out on strips of aorta obtained from immunized and control animals. Immunization with elastin peptides significantly increased the ouabain-insensitive 22Na+ efflux, the 86Rb efflux (indicator of K+ efflux), and the 45Ca2+ influx. Simultaneous calcitonin administration prevented the increase in Ca2+ influx but did enhance passive permeability to Na+ and K+ as well as the sodium pump. When calcitonin was administered without immunization, it decreased arterial smooth muscle permeability to Na+ and K+ and also decreased the basal Ca2+ influx. It is concluded that the pathological modifications of the arterial wall triggered by immunization with elastin peptides is at least partly mediated by the effect of antielastin antibodies and immune complexes on the ion permeability of arterial smooth muscle. Prevention of the increased Ca2+ influx by calcitonin is probably a key effect in the prevention of the development of lesions. The fact that calcitonin alone can modify the ion permeability of arterial smooth muscle suggests that this hormone may play a role in the regulation of vascular homeostasis.
Exp Mol Pathol 1987 Jun
PMID:Prevention by calcitonin of the pathological modifications of the rabbit arterial wall induced by immunization with elastin peptides: effect on vascular smooth muscle permeability to ions. 243 69

Six rat monoclonal antibodies to mouse lung membrane fraction have been characterized. Each has unique binding properties and can be used to stain particular lung components in paraffin sections. One antibody, 133-13A, recognizes a 100-kDa glycoprotein on lung tumor cells, but stains only macrophage-like cells in normal or fibrotic lung sections as determined by immunogold electron microscopy. The monoclonal antibody 273-34A binds to a 112-kDa protein on the surface of normal mouse lung fibroblasts. Immunogold electron microscopy demonstrates antibody binding to capillary endothelial cells, but not to fibroblasts. Type I, or Type II cells. Staining of fibrotic sections with MoAb 273-34A is dramatically enhanced over staining of normal lung. A third antibody, 370-8A, gives a general staining pattern throughout normal lung that is intensified in fibrotic lung. Another MoAb 328-41A mediates intense nuclear fluorescence of lung tumor cells and cells in lung sections. It binds to 14- and 17-kDa proteins that may be high mobility group (HMG) nuclear proteins. Enzyme inhibition studies and immunofluorescence staining patterns on normal lung indicate that elastin may be the target of MoAb 328-35B. MoAb 327-5B binds to normal mouse lung fibroblasts and red blood cell membranes. These last three MoAbs stain macrophages in fibrotic lung, but give a general pattern of light epithelial cell stain in normal lung sections indicating macrophage engulfment of the normal cell antigen during fibrosis. These antibodies should be useful in identifying cell types and molecular mechanisms involved in early stages of fibrosis induced by different chemical insults.
Exp Mol Pathol 1987 Aug
PMID:Rat monoclonal antibodies to mouse lung components for analysis of fibrosis. 244 Jul 15

An analysis of the structure of chicken vitreous humor after brief homogenization of the tissue was performed. Electron micrographs prepared after rotary shadowing with platinum showed the presence of two distinct fibrils. The collagen fibril was coated by glycosaminoglycan which could be removed by chondroitinase ABC digestion. In addition, individual molecules of tenascin were observed wrapped around some of the collagen fibrils. A second beaded fibril was present and several fine filaments were observed to extend from each bead. The beaded fibril is formed by the overlap of these filaments, and beaded fibrils were observed in either a "closed" or an "open" form dependent on whether all of the filaments are brought together to form the overlap. A schematic diagram is presented for the structure of the beaded fibril. The potential relationship of the beaded fibril to the zonular fibrils and the elastin microfibrils is briefly discussed.
J Ultrastruct Mol Struct Res 1988 Sep
PMID:Vitreous humor of chicken contains two fibrillar systems: an analysis of their structure. 246 20

The pathogenesis of monocrotaline-induced pulmonary hypertension is not clear. Progressive pulmonary arteritis leading to vascular sclerosis, narrowing of the lumina, and thrombosis is the suspected sequence. To investigate this, we examined the effect of isosorbide dinitrate (ISDN), prednisolone, indomethacin, and elastase in 100 SD male rats, 4 weeks after the injection of monocrotaline (MCT) by cardiac catheterization, right ventricle-to-left ventricle plus septum weight ratio (RV/LV + S), histology, and electron microscopy. ISDN, a vasodilator, reduced the elevation of right ventricular (RV) pressure, RV/LV + S, and also pulmonary vascular remodeling; the characteristic histological feature was dilatation of small pulmonary arteries. Both prednisolone and indomethacin reduced RV pressure, RV/LV + S, and pulmonary vasculitis. Elastase, a protease which controls the metabolism of elastin in the arterial wall, likewise reduced RV pressure, RV/LV + S, and pulmonary vascular remodeling, with a significant decrease in elastosis of the small pulmonary arteries histologically. We concluded that all of the pathological processes resulting from arteritis are important in the development of MCT-induced pulmonary hypertension. In all experimental groups, decreased histopathologic changes correlated with decrease in the pressure. Elastase, which reduces pulmonary arterial sclerosis, is suggested as a new agent to treat pulmonary hypertension.
Exp Mol Pathol 1989 Jun
PMID:Comparative effects of isosorbide dinitrate, prednisolone, indomethacin, and elastase on the development of monocrotaline-induced pulmonary hypertension. 249 22

Neonatal calves exposed to chronic hypobaric hypoxia develop severe pulmonary hypertension associated with altered vascular reactivity, cellular proliferation, and increased elastin and collagen production. We hypothesized that prostaglandin (PG) production would be decreased in the pulmonary arterial vessel wall of these calves. Further, because of the possibility that the hemodynamic stresses of hypoxic pulmonary hypertension might change along the longitudinal axis of the pulmonary circulation, we measured prostaglandin synthetic capability in tissues isolated from proximal pulmonary artery, distal pulmonary artery, and pulmonary vein. We found that PGI2 production was decreased in both proximal and distal pulmonary artery rings isolated from pulmonary hypertensive calves compared to controls. PGI2 production was greater in distal than in proximal lobar pulmonary artery. In contrast, pulmonary veins from hypertensive calves, which are protected from the hemodynamic stress of pulmonary arterial hypertension, did not demonstrate altered PGI2 production compared to controls. PGE2 production was also decreased in proximal hypertensive pulmonary arterial rings as compared to controls. To determine if this decrease in vessel wall production of prostaglandins was due to changes in cellular prostaglandin production, we studied prostaglandin production by the three major cell types comprising hypertensive and control arteries. Endothelial cells cultured from hypertensive main pulmonary artery produced less PGI2 than did those from control artery, and there appeared to be a shift from PGI2 production to PGE2 production in endothelial cells isolated from hypertensive artery. Explanted advential fibroblasts from hypertensive artery produced less PGE2 than did controls. Smooth muscle cell PGI2 production did not differ between cells isolated from hypertensive and control arteries in these brief 30-min incubations. We conclude that there is a relative deficit in PGI2 and PGE2 production in the pulmonary arteries of calves with hypoxia-induced pulmonary hypertension and speculate that this contributes to altered vascular tone and vessel remodeling.
Am J Respir Cell Mol Biol 1989 Dec
PMID:Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. 251 77

Neutrophils were found to demonstrate chemotactic responses to pepsinized human placental type IV collagen and its purified aminoterminal 7S domain. The maximal chemotactic responses occur at approximately 400 ng/ml and approximately 30 ng/ml of type IV collagen and 7S collagen, respectively, and are similar in magnitude to the chemotactic response of neutrophils to 10(-8) M FMLP. Human leukemic cells of the HL 60 line display chemotaxis to type IV collagen and 7S collagen only after they are differentiated along the neutrophilic pathway with dimethyl sulfoxide. When detergent extracts of neutrophils are applied to type IV collagen-Affi-Gel resin, a 67 kD protein is retained by the resin and is eluted with guanidine/octyl-beta-glucoside or lactose. This 67 kD polypeptide has an amino acid composition resembling the 67 kD component of the elastin receptor complex, displays immunologic cross-reactivity with antibody to the 67 kD component of the elastin receptor, and binds to elastin and laminin affinity resins. Neutrophil chemotaxis to type IV collagen and 7S collagen is selectively abolished by exposing the test neutrophils to lactose or elastin peptides. We conclude that neutrophils may migrate in vivo to proteolytic fragments of type IV collagen and that this response may be mediated by a lectin-like protein that is similar to the 67 kD component of the elastin receptor.
Am J Respir Cell Mol Biol 1989 Dec
PMID:Neutrophils show chemotaxis to type IV collagen and its 7S domain and contain a 67 kD type IV collagen binding protein with lectin properties. 256 90

Alpha-1-antitrypsin (AAT) is the predominant protease inhibitor in human sera. The major physiological role of this inhibitor is to protect elastin fibers in the alveolar structure of the lung from excessive degradation by neutrophil elastase. AAT is synthesized predominantly by hepatocytes, although the AAT gene is expressed to a small degree in the epithelial cells of various tissues. Recent studies have shown that the enhanced liver-specific expression of the AAT gene is controlled by the binding of hepatic nuclear proteins to specific DNA sequences upstream from the structural gene. A variety of mutations within the AAT gene have been identified that result in a partial deficiency or total absence of the inhibitor in sera. Inheritance of a particular combination of these alleles can result in a predisposition towards the development of destructive lung disease. Interestingly, the most common AAT deficiency variant, designated PiZ, causes the mutant protein to accumulate as an insoluble aggregate within the lumen of the hepatic rough endoplasmic reticulum, which is an etiological agent for the development of liver disease. Overall, investigation into the genetic control of AAT has led to an increased understanding of the factors that control hepatic gene expression, as well as mechanisms involved in the pathophysiology of emphysema and liver cirrhosis.
Mol Biol Med 1989 Apr
PMID:Genetic control of human alpha-1-antitrypsin. 269 88

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. In the present study, the development of emphysema was investigated in these mice with histological, biochemical, and ultrastructural methods at 4 days and at 1 and 2 months of life. At 4 days after birth, histological examination of the lungs revealed only a mild enlargement of the primary sacculi. Neither biochemical nor ultrastructural changes were seen however at this time. At 1 month of age, the histological examination showed marked emphysema-like changes, characterized by enlargment of air spaces accompanied by destruction of alveolar walls. Biochemical analysis showed a marked decrease in insoluble elastin content and a significant increase in salt-extractable collagen. Ultrastructural investigation revealed edema fluid in the interstitium and broken and disorganized elastic fibers. All these findings strikingly resemble the changes which occur in the lungs early after an instillation of elastase. In the 2-month-old Tsk mice the histological lesion progressed in severity. The ultrastructural findings were similar to those observed at 1 month, and the biochemical changes showed no signs of recovery. Thus, in these mice, the emphysematous lesion develops very rapidly between 4 days and 1 month of life and shows the characteristics of an elastolytic process which is still ongoing at 2 months of age.
Exp Mol Pathol 1989 Jun
PMID:A biochemical and morphological investigation of the early development of genetic emphysema in tight-skin mice. 272 56

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. A morphometric study has shown that emphysema develops quickly, between 15 days and 1 month after birth. Previous biochemical and ultrastructural investigations of the lungs of 1- and 2-month-old Tsk mice revealed the presence of an ongoing elastolytic process. The goal of the present study was to investigate the role of mouse leukocyte elastase (MLE) in the development of emphysema in 1-month-old Tsk mice. Using electron microscopy and an immunogold labeling technique with rabbit anti-MLE IgG, MLE was localized within the lung neutrophils of control and Tsk mice. MLE was also found associated with elastin in the alveolar septa of Tsk but not of control mice. Little or no labeling was associated with other components (collagen, pneumocytes, and endothelium) of alveolar septa of Tsk mice. Lung elastin of control mice, or of control mice rendered emphysematous with porcine pancreatic elastase, showed negligible gold particle density when incubated with gold-conjugated rabbit IgG. Thus, under the present experimental conditions, an aspecific labeling of elastin is unlikely. This study indicates that MLE may be one of the factors responsible for the rapid development of emphysema in Tsk mice.
Exp Mol Pathol 1989 Aug
PMID:Immunoelectron-microscopic demonstration of elastase in emphysematous lungs of tight-skin mice. 276 16


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