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)

The cysteinyl leukotrienes (CysLTs) mimic many of the features of asthma and are implicated in its pathophysiology. Little, however, is known about the effects of the CysLTs on airways remodeling. In this study the effects of leukotriene D4 (LTD4) on human airway smooth muscle (HASM) cell proliferation and expression of extracellular matrix proteins were investigated. LTD4 (0.1-10 microM) alone had no effect on DNA synthesis in HASM. LTD4, however, markedly augmented proliferation induced by the mitogen, epidermal growth factor (EGF, 1 ng/ml). The potentiating effect of LTD4 (1 microM) on EGF-induced DNA synthesis was abolished by pranlukast (1 microM) or pobilukast (30 microM), but unaffected by zafirlukast (1 microM). In contrast, pranlukast (pKB = 6.9), pobilukast (pKB = 7.0), and zafirlukast (pKB = 6.5) had equivalent potencies for inhibition of LTD4-induced contraction in human bronchus. LTD4 (0.1 or 10 microM) did not increase the total messenger RNA expression of the extracellular matrix proteins (pro-alpha[I] type I or alpha1[IV] type IV collagen), elastin, biglycan, decorin, and fibronectin, and did not influence tumor growth factor-beta (10 ng/ml)-induced effects on the expression of these proteins in HASM cells. These data indicate that LTD4 augments growth factor-induced HASM proliferation but does not alter the expression of various extracellular matrix components. The observed differences in sensitivity to the antagonists suggests that the former phenomenon may be mediated by a CysLT receptor distinct from that which mediates LTD4-induced HASM contraction. Collectively, these results provide preliminary evidence that CysLTs may play a role in airways remodeling in asthma.
Am J Respir Cell Mol Biol 1998 Sep
PMID:Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction In vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. 973 Aug 73

Elastin is a major protein component of the vascular wall and is responsible for its unusual elastic properties. Polymers of its repeating VPGVG sequences have been synthesised and shown to exhibit an inverse temperature transition where, as temperature rises, the polymer collapses from an extended chain to a beta-spiral structure with three VPGVG units per turn, each pentamer adopting a type II beta-turn conformation. These studies, however, have not established whether the temperature-driven conformational change is an intrinsic property of the individual pentameric sequences or a global, co-operative effect of many pentamers within the beta-spiral structure. Here, we examine by circular dichroism the behaviour of elastin-like peptides (VPGVG)n, where n varies between 1 and 5. Remarkably, we find that all lengths of peptide undergo an extended left and right arrow beta-turn transition with increasing temperature, suggesting that the induction of the beta-spiral occurs at the level of single pentameric units. The origin of this effect is a positive DeltaS term for the transition. At 35 degreesC, the average transition midpoint temperature, the value of TDeltaS is about 15 kcal mol-1. With larger oligomers (n=3), there is only a modest rise in DeltaS, suggesting that the dominant entropic effect resides within the monomer and that interactions between these units make only a small contribution to the energetics of the transition. Charges at the termini, and residue replacements or additions, regulate the transitions for the short peptides in a manner similar to that observed for the longer polymers. The behaviour of the same peptides in trifluoroethanol and SDS solutions is consistent with formation of the beta-turn being driven by interactions between non-polar groups. The significance of this behaviour for the rational design of temperature-induced responses in proteins is discussed.
J Mol Biol 1998
PMID:Short elastin-like peptides exhibit the same temperature-induced structural transitions as elastin polymers: implications for protein engineering. 976 88

The collagen-elastin-proteoglycan (PG) matrix is the key constituent of lung parenchyma and plays a major role in the mechanical behavior of lung tissues. However, the exact composition of the PG matrix in lungs has not yet been fully determined. In the present study we report the expression of leucine-rich repeat PGs in adult human lungs. PG extraction was performed on peripheral lung tissue from patients undergoing therapeutic lung resections. The samples were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting using antipeptide antisera specific to human lumican, decorin, biglycan, and fibromodulin. Control experiments to verify antiserum reactivity were performed with an extract of adult human articular cartilage, which is known to contain all four PGs. In all lung extracts analyzed, a single component of molecular weight 65 to 90 kD was detected for lumican. Decorin, biglycan, and fibromodulin were either not detected or were barely detectable in the lung extracts, but were readily visualized in the cartilage samples. Immunohistochemistry showed that lumican was diffusely present in peripheral lung tissue, mainly in vessel walls. These results suggest that lumican is a major component of the PG matrix in adult human lungs.
Am J Respir Cell Mol Biol 1998 Oct
PMID:Expression of lumican in human lungs. 976 54

The cytokine transforming growth factor-beta has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In the present work, we demonstrate that TGF-beta1 increases transcription of the latent transforming growth factor-beta binding protein-2 ( LTBP-2) gene in cultured human fetal lung fibroblasts leading to a significant increase in LTBP-2 mRNA steady state level. The stability of LTBP-2 mRNA was not appreciably altered. A corresponding increase in production of LTBP-2 protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that a member of the Ras super family and a protein kinase C, probably of the atypical (non-diacylglycerol, non-Ca++ dependent) class are likely to be components in the signaling pathway. However, phospholipases, G proteins and extracellular-signal regulated kinases do not appear to be involved. These results combined with previous findings on elastin regulation by TGF-beta1 (Kucich et al. (1997). Am. J. Respir. Cell Mol. Biol., 17: 10-16) demonstrate that TGF-beta1 can coordinately increase the steady state levels of mRNAs encoding components of the elastic fiber, but through diverse mechanisms. In contrast to LTBP-2, increased elastin expression is achieved by message stabilization. Furthermore, the TGF-beta1 signaling pathways differ and while the pathway leading to increased LTBP-2 transcription shares components with those modulating transcription of other genes, it is unlikely to be precisely congruent with any other previously described one.
 ...
PMID:Signaling pathway by which TGF-beta1 increases expression of latent TGF-beta binding protein-2 at the transcriptional level. 986 26

The beige mouse is currently used as a model of elastase and cathepsin G deficiency to demonstrate or exclude the role of these proteases in a variety of pathologic conditions. We recently demonstrated that beige cathepsin G is tightly bound to neutrophil lysosomal membranes but is released in near normal quantities during exocytosis. Also, beige neutrophils contain a latent form of elastase that undergoes spontaneous activation when released under in vitro or in vivo conditions. However, the pathogenic potential of this enzyme in matrix degradation has not been ascertained previously. The possibility that in beige mice elastolytic proteases from neutrophils recruited into the lung have the capability to damage alveolar septa was investigated following an intratracheal instillation of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (200 microg). Neutrophil influx was followed by a decrease in lung elastin content (-18%) and by a significant increase of the mean linear intercept (+30%) and of morphologic emphysema. The onset of pulmonary lesion was preceded by a marked increase of neutrophil elastase burden on the alveolar interstitium. The appearance of emphysema was prevented by administration of the serine protease inhibitor 4-(2-aminoetyl)-benzenesulfonyl fluoride hydrochloride (2. 4 microg/ml saline). These results demonstrate that the lung elastin degradation and emphysema can occur in beige lungs. The fact that the beige mouse does develop lung elastolytic changes after neutrophil recruitment indicates that this mutant cannot be considered a model of neutrophil function deficiency and used as a model of elastase deficiency.
Am J Respir Cell Mol Biol 1999 Feb
PMID:Neutrophil influx into the lungs of beige mice is followed by elastolytic damage and emphysema. 992 17

In fetuses with diaphragmatic hernia (DH) lung development is impaired, and pulmonary hypoplasia is one of the main factors responsible for the poor outcome of the disease. A possible treatment consists of occluding trachea during lung development to retain pulmonary fluid and to force the lung to expand. Although it appeared promising at first, this technique has recently been reported to decrease type II cell number and to induce surfactant deficiency. The aim of this study was to investigate lung maturation further through ultrastructural examination in a fetal lamb model of DH created at 85 d, followed or not by endoscopic balloon tracheal occlusion (TO) at 120 d of gestation. The proportion of alveolar epithelial type I and type II cells was altered by both treatments: the type I/type II cell ratio, which was about 2 in control lungs, was decreased 4.5-fold in DH lungs but was increased 4.5-fold in DH+TO lungs. The proportion of undifferentiated cells was increased in DH lungs. Indeterminate cells sharing features of type II and type I cells that were not observed in controls were seldom seen in DH lungs and were numerous in DH+TO lungs. The number of lamellar bodies per type II cell was decreased in both DH and DH+TO groups. In DH lungs, wall structure presented an immature appearance, with cellular connective tissue and poor secondary septation of saccules. In DH+TO lungs, primary septa appeared more mature, with reduced connective tissue, but secondary septa were still buds, although elastin was present at their tips. A single capillary layer was found in all three groups (control, DH, and DH+TO) with no sign of septal capillary pairing. This first investigation in DH and DH+TO lungs through transmission electron microscopy thus enabled us to show that compression and forced expansion of the lung are both responsible for alterations in type II cell differentiation and septal development.
Am J Respir Cell Mol Biol 1999 Apr
PMID:Ultrastructural evaluation of lung maturation in a sheep model of diaphragmatic hernia and tracheal occlusion. 1010 Oct 14

We have reported two hypothetical proteins of human aorta, based on sequences cloned from a cDNA library constructed from mRNAs purified from the adventitia. These sequences have immunoglobulin-kappa (IgK)-like domains, and we have shown that microfibrils of the aortic adventia are immunoreactive with antibodies against IgK. The present study was performed to characterize more specifically the regional distribution in human of one of these proteins in particular and the distribution of matrix proteins with IgK-like motifs in general. An antibody was raised in rabbit against a synthetic peptide based on a unique sequence in one of the hypothetical proteins (NPSNRVTPQKNFP), which has not been reported in the sequence of any other known protein. This antibody and a rabbit anti-human IgK antibody were used as first antibodies in the staining reactions. A monoclonal mouse anti-smooth muscle cell alpha-actin antibody was also used. Immunoreactivity with the sequence-specific antibody was limited to the aorta and large vessels. Adventitial microfibrillar staining was more conspicuous in the abdominal aorta than in the thoracic aorta and in the internal iliac than in the external iliac artery. The immunoreactive protein was associated with fibroblasts and not smooth muscle cells. Immunoreactivity coated the collagen fibers diffusely, while elastin fibers were not stained. Further studies using antibodies against IgK demonstrated immunoreactivity of collagen and fibroblasts in a variety of tissues: spleen, ovary, testicle, cervix, prostate, skin, and breast (but not brain). Immunoglobulin motifs may be a feature of matrix proteins produced by fibroblasts in many tissues, but the first motif that we identified from a cDNA library of aortic adventitia appears to be specific to aorta and large vessels.
Exp Mol Pathol 1999 Apr
PMID:Regional distribution in human of a novel aortic collagen-associated microfibrillar protein. 1033 65

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
Am J Respir Cell Mol Biol 1999 Jun
PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32

Lung elastin synthesis is normally confined to periods of development, is maximal during alveolarization, and declines to low levels in mature lung. We have previously described an elastogenic response in the adult rat lung associated with experimental granulomatous disease induced by silica instillation. Reinitiated tropoelastin expression was identified throughout the lung in fibroblasts expressing alpha-smooth-muscle actin, whereas fibroblasts within the granulomatous lesions failed to express both tropoelastin and alpha-smooth- muscle actin (Mariani and colleagues, Am. J. Pathol. 1995;147:988-1000). We hypothesized that inflammatory cells within the granulomatous lesions produce factors that alter fibroblast phenotype. We found that macrophages accumulating within granulomatous lesions of silicotic rat lungs produce and secrete tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine previously appreciated as a repressor of tropoelastin gene expression. In experimental cell systems, macrophages activated by particulates, either in vivo or in vitro, conditioned medium with a tropoelastin-repressing activity. This activity repressed both tropoelastin and alpha-smooth-muscle actin expression in primary cultures of rat lung fibroblasts in a time- dependent, transient manner. The particulate-activated macrophage-conditioned medium was found to contain TNF-alpha, which was both necessary and sufficient to induce these changes in lung fibroblast gene expression. These data indicate that macrophage-derived factors can modulate lung fibroblast tropoelastin expression in the diseased lung. Furthermore, the findings extend the association between expression by lung fibroblasts of tropoelastin and alpha-smooth-muscle actin.
Am J Respir Cell Mol Biol 1999 Aug
PMID:Fibroblast tropoelastin and alpha-smooth-muscle actin expression are repressed by particulate-activated macrophage-derived tumor necrosis factor-alpha in experimental silicosis. 1042

In cystic fibrosis (CF), the intense host inflammatory response to chronic infection largely accounts for the progressive pulmonary disease, and ultimately death. Neutrophils are the prominent inflammatory cells in the lungs of patients with CF, and large amounts of neutrophil elastase (NE) are released during phagocytosis. Besides having direct effects on structural elastin, NE stimulates the release of proinflammatory mediators from the respiratory epithelium and is a potent secretogogue. Therapeutic use of elastase inhibitors in CF has been complicated by difficulties in delivery to the critical site in the airway-the surface of the epithelium. We describe a unique strategy to protect the respiratory epithelial cell surface directly by capitalizing on the nondegradative transcytotic pathway of the polymeric immunoglobulin receptor (pIgR). A recombinant fusion protein was constructed consisting of an antihuman pIgR single-chain Fv (scFv) antibody linked to human alpha(1)-antitrypsin (A1AT), an inhibitor of NE. The recombinant scFv-A1AT fusion protein bound specifically to the pIgR on the basolateral surface of an epithelial cell monolayer, and was transported and released into the apical medium where the A1AT domain was capable of forming an inactivation complex with NE. Thus, A1AT linked to an antihuman pIgR scFv was delivered in receptor-specific fashion from the basolateral to apical surface and was released as an active antiprotease, indicating that it is feasible to deliver therapeutic proteins to the apical surface of epithelia by targeting the pIgR.
Am J Respir Cell Mol Biol 1999 Aug
PMID:In vitro transport of active alpha(1)-antitrypsin to the apical surface of epithelia by targeting the polymeric immunoglobulin receptor. 1042 8


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