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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary cultures of guinea pig tracheal epithelial cells maintained in an air/liquid interface system that maintains differentiated characteristics were grown to near confluence and exposed for 1 h to platelet-activating factor (PAF) on both apical and basal sides. PAF provoked release of high-molecular-weight mucin-like glycoproteins (MLG) from the cells, with maximal stimulation occurring at 10(-8) and 10(-9) M. The inactive form of PAF, lyso-PAF, was without effect. Indomethacin, the cyclooxygenase inhibitor, did not affect secretion stimulated by PAF, but nordihydroguiaretic acid (NDGA), a mixed cyclooxygenase and lipoxygenase inhibitor, attenuated secretion stimulated by PAF in a concentration-dependent manner. High performance liquid chromatography assay of the culture medium after addition of PAF revealed increased production of 15-, 12-, and 5-hydroxyeicosatetraenoic acids (15-, 12-, and 5-HETEs). The stimulatory effect of PAF on both mucin secretion and formation of HETEs was inhibited by the PAF receptor antagonists, CV-3988 and Ro 19 3704, with Ro 19 3704 acting at a concentration 10-fold lower than CV-3988 in inhibiting both effects. When added exogenously to the cell cultures, the combination of 5-, 12-, and 15-HETEs stimulated MLG release in a concentration-dependent manner. The results suggest that PAF stimulates release of MLG by guinea pig airway epithelium in vitro by a mechanism involving binding of PAF to receptors on epithelial cell surfaces, stimulation of lipoxygenase metabolism of arachidonic acid to HETEs within the epithelium, and stimulation of secretion by these epithelial-derived HETEs via an autocrine or paracrine mechanism.
Am J Respir Cell Mol Biol 1992 May
PMID:Platelet-activating factor provokes release of mucin-like glycoproteins from guinea pig respiratory epithelial cells via a lipoxygenase-dependent mechanism. 131 34

HeLa cells attach to a variety of substrata but spread only on collagen or gelatin. Spreading is dependent on collagen-receptor upregulation, clustering, and binding to the cytoskeleton. This study examines whether second messengers are involved in initiating the spreading process on gelatin. The levels of cytosolic free calcium ([Ca++]i), cAMP, and cytoplasmic pH (pHi) do not change during cell attachment and spreading. However, a basal level of [Ca++]i and an alkaline pH(i) are required for spreading. There is an activation of protein kinase C (PKC) and a release of arachidonic acid (AA) on attachment and before cell spreading. Inhibition of PKC does not block cell spreading, indicating that PKC activation is not essential for spreading. Inhibition of phospholipase A2 blocks cell spreading, whereas addition of exogeneous AA overcomes this inhibitory effect. Among AA metabolic pathways, inhibitors of lipoxygenase (LOX) block cell spreading, suggesting that a LOX product(s) formed from AA initiates spreading. Clustering receptors for collagen with polyclonal antibodies, or with anti-collagen-receptor antigen-binding fragments (Fab) in combination with a secondary antibody, induce AA release. Also, AA is released when cells attach to either immobilized gelatin or immobilized Arg-Gly-Asp (RGD) peptide. Thus, AA is released whenever receptor clustering is observed. Receptor occupancy is not sufficient to release AA; when cells are treated with gelatin or RGD peptide in solution or anti-collagen-receptor Fab fragments without secondary antibody, conditions where receptor clustering is not observed, AA is not released. Thus, a LOX metabolite(s) of AA formed by collagen-receptor clustering is a second messenger(s) that initiates HeLa cell spreading. LOX inhibitors also block the spreading of bovine aortic endothelial cells, chicken embryo fibroblasts, and CV-1 fibroblasts on gelatin or fibronectin, indicating that other cells might use the same second messenger system in initiating cell-substratum adhesion.
Mol Biol Cell 1992 May
PMID:Spreading of HeLa cells on a collagen substratum requires a second messenger formed by the lipoxygenase metabolism of arachidonic acid released by collagen receptor clustering. 131 41

Exposure of rats to ozone (O3) produces an increase in airway permeability and a concomitant influx of polymorphonuclear leukocytes in the lung. These observations raise the possibility that the inflammatory cells play a role in the cellular injury and increased airway permeability after O3 exposure. This study was therefore designed to determine if the inflammatory cells or their products are essential for the O3 effect. In a series of experiments, rats were rendered leukopenic with cyclophosphamide, treated with leukotriene B4 (LTB4), or with the inhibitors of lipoxygenase or cyclooxygenase products of arachidonic acid, followed by exposure to O3. A 2-h exposure to 0.8 ppm O3 caused a significant increase in the flux of proteins and albumin in bronchoalveolar lavage (BAL) and elevated the transport of 99mTc-diethylenetriaminepentaacetate (99mTc-DTPA) from trachea to blood. The treatment with cyclophosphamide caused a significant reduction in the circulating and pulmonary leukocytes and prevented an increase in tracheal mucosal permeability to 99mTc-DTPA and the protein and albumin flux in BAL. While the intratracheal instillation of LTB4 did not affect the permeability, tracheal permeability and albumin levels in BAL in rats treated with LTD4 antagonist FPL 55712 and exposed to O3 were lower than in the untreated O3-exposed rats. Pretreatment with indomethacin also prevented the O3 effects, as reflected by the decreased protein and albumin flux in BAL and 99mTc-DTPA transport from trachea to blood. These data show a reduction in the effect of O3 by agents that affect leukocytes or their products. The results support a mechanism of increased permeability that is dependent upon inflammatory cells and their products.
Am J Respir Cell Mol Biol 1992 Jul
PMID:Attenuation of ozone-induced airway permeability in rats by pretreatment with cyclophosphamide, FPL 55712, and indomethacin. 132 Sep 4

Lipoxygenase metabolites influence ion movement and fluid balance in the airways. We studied the effects of nordihydroguaiaretic acid (NDGA), a general inhibitor of the lipoxygenase pathway, on Na+ and Cl- secretion in cultured tracheal epithelial cells from adult rabbits through short-circuit current (Isc) and radioactive tracer flux experiments. NDGA inhibition of leukotriene release in freshly isolated rabbit tracheal epithelial cells was assayed by a 3H peptidyl-leukotriene radioimmunoassay. 3 microM NDGA resulted in a 91% reduction of leukotriene release. In unstimulated cultures, Cl- secretion (furosemide-inhibited fraction of Isc) was 11.1 +/- 2.8 muamp/cm2 (n = 10) and was unchanged in the presence of NDGA (n = 10). Epinephrine-stimulated Cl- secretion increased Isc by 12.2 +/- 2 muamp/cm2 (n = 10). This stimulation was unchanged by pretreatment with NDGA (n = 10), suggesting that inhibition of the lipoxygenase pathway did not affect Cl- secretion. In unstimulated cultures, Na+ absorption (amiloride-inhibited portion of Isc) was 10.7 +/- 3.3. muamp/cm2 (n = 10) and was reduced by 79% in the presence of NDGA (n = 10), suggesting that inhibition of the lipoxygenase pathway was associated with inhibition of Na+ absorption. Radioactive tracer flux experiments supported these findings. Exogenous LTD4 (n = 7) and LTC4 (n = 7) were added to cells pretreated with NDGA, and Na+ absorption was restored to 76% and 70% of control, respectively. In addition, LTD4 (n = 4) and LTC4 (n = 4) were added to cells without prior inhibition of the lipoxygenase pathway to NDGA and resulted in an increase in Cl- secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Nov
PMID:Modulation of ion transport in cultured rabbit tracheal epithelium by lipoxygenase metabolites. 141 26

The condensed tannin present in cotton mill dust profoundly alters the functional capabilities of resident alveolar macrophages. Previous studies from this laboratory have shown that in vitro exposure of rabbit resident alveolar macrophages to condensed tannin significantly inhibits the ability of these cells to produce reactive oxygen intermediates or to ingest particles. In the present study, we demonstrate that condensed tannin also alters arachidonic acid (C20:4) metabolism in these cells. Exposure of rabbit resident alveolar macrophages to condensed tannin results in the time- and dose-dependent release of C20:4 from the membrane phospholipids. The release of C20:4 occurred only at tannin concentrations greater than 25 micrograms/ml and was maximal 90 min after the onset of exposure. The EC50 for release was 75 micrograms/ml. Exposure to 100 micrograms/ml tannin resulted in the release of 20 +/- 3% of the [14C]C20:4 incorporated in the cell membrane. In comparison, exposure to 160 micrograms/ml zymosan resulted in the release of 14 +/- 4% of the [14C]C20:4. For both tannin and zymosan, phosphatidylcholine and phosphatidylinositol were the principal sources of the released C20:4. Approximately 63% of the C20:4 released after zymosan stimulation was further metabolized, mainly via the cyclooxygenase pathway. The major metabolites were 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin E2. In contrast, only 24% of the C20:4 released by tannin was subsequently further metabolized. The metabolites formed were essentially evenly distributed between products of the cyclooxygenase pathway and the lipoxygenase pathway. Exposure of alveolar macrophages to 50 micrograms/ml tannin for 30 min reduced the ability of the cells to subsequently incorporate C20:4 by 50 to 70%. In contrast, exposure of the cells to 160 mg/ml zymosan for 30 min had only a minimal effect on the subsequent ability of these cells to incorporate C20:4. These results indicate that tannin promotes C20:4 release, at least in part, by inhibiting its reacylation back into phospholipids, a mechanism that differs from that of zymosan.
Am J Respir Cell Mol Biol 1992 Aug
PMID:Condensed tannin promotes the release of arachidonic acid from rabbit resident alveolar macrophages. 149 6

Our object was to obtain information about the regulatory mechanism which modulates the effect of basic fibroblast growth factor (bFGF) on commitment to growth in human umbilical vein endothelial (HUVE) cells. Firstly, phorbol ester PMA, a known activator of protein kinase C (PKC), was found to be able to act synergistically with bFGF to stimulate 3H thymidine incorporation in HUVE cells. Secondly, bFGF and PMA induced a stimulated phospholipase A2 (PLA2)-catalyzed release of 14C arachidonate. Thirdly, inhibitors of PLA2, PKC and HETE, but not an inhibitor of cyclooxygenase metabolites, inhibited FGF/PMA-stimulated DNA synthesis. Fourth, the stable cyclooxygenase metabolite of prostacyclin was not found to be changed when cells were treated with bFGF plus PMA. The present data suggest that PKC is able of acting synergistically with bFGF in order to stimulate DNA-primary initiation activity in HUVE cells via the PLA2-dependent generation of lipoxygenase metabolites such as HETE.
Cell Mol Biol 1992 Jul
PMID:Possible involvement of arachidonic acid metabolites in the synergistic action of endothelial mitogenesis by basic fibroblast growth factor and phorbol ester. 149 42

Mucus production is an integral component of airway mucosal inflammation. Platelet-activating factor (PAF) is a phospholipid mediator implicated in the pathogenesis of many inflammatory processes, including airway inflammation. PAF functions as a mucus secretagogue when mucus is quantitated as radiolabeled glycoconjugates released from airway organ cultures. To more directly assess the interaction of PAF and airway epithelial mucous cell secretion, we used primary feline tracheal epithelial cell cultures and an immunoassay for a specific mucous cell secretory vesicle component. Cultured tracheal epithelial cells were shown to synthesize and secrete glycoconjugates with mucin characteristics. These mucin-type glycoconjugates were immunoreactive with a mucous cell-specific antibody. Localization of this antibody to components of the secretory vesicles of cultured epithelial cells was confirmed by electron microscopic immunogold labeling. Using this monoclonal antibody, an immunoassay was developed to quantitate release of immunoreactive material into cell culture media. Exposure of cultures to PAF produced a concentration-dependent, prompt release of immunoreactive material. Concentration-dependent inhibition of this effect was demonstrated by coincubation with the PAF receptor antagonists, WEB 2086 and Ro 19-3704. A component of the signal transduction pathway for PAF effects was studied in cultured tracheal epithelial cells by coincubation of PAF with nordihydroguaiaretic acid (NDGA), a combined lipoxygenase and cyclooxygenase inhibitor, or p-bromophenacyl bromide (BPB), an inhibitor of cellular arachidonic acid release. Both NDGA and BPB blocked PAF-stimulated mucin release in a concentration-dependent manner. These studies demonstrate a direct airway epithelial mucous cell secretagogue effect that appears to be dependent upon airway epithelial PAF receptors and altered cellular lipid metabolism. These findings suggest a direct and potent mechanism for goblet cell secretion during airway inflammation.
Am J Respir Cell Mol Biol 1992 Feb
PMID:Airway epithelial cell mucin release: immunologic quantitation and response to platelet-activating factor. 154 Mar 79

T lymphocytes from T. cruzi infected mice susceptible to the development of myocarditis altered the contractility of normal mouse atria in vitro. While lymphocytes obtained from normal mice had no effect, lymphocytes from T. cruzi-infected mice cultured with normal atria induced negative or positive inotropic effects depending upon the post-infection period; negative inotropism was induced by lymphocytes obtained from animals at 1 to 4 weeks post-infection, and positive inotropism was induced by lymphocytes taken at 7 to 14 weeks post-infection. These effects were mediated by soluble factors as evidenced by the ability of lymphocyte culture supernatants to alter contractility. Cell enrichment experiments indicated that T lymphocytes rather than B lymphocytes were responsible for these inotropic effects. Lyt(2+)-enriched T lymphocytes were found to be responsible for triggering the negative inotropic effect at 3 weeks post-infection when myocarditis was less intense, whereas Lyt1(+)-enriched T lymphocytes induced the positive inotropic effect at 8 weeks after T. cruzi infection when myocarditis was severe. Furthermore, inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism blunted the negative inotropic effect while inhibitors of lipoxygenase pathway inhibited the positive inotropic effect. PGE2 was found to be spontaneously released by Lyt(2+)-enriched T cells obtained at 3 weeks post-infection while LTC4 was released by atria cultured in the presence of Lyt 1+ T cells obtained at 8 weeks post-infection. In conclusion, these findings suggest that infiltrating T lymphocytes may contribute to myocardial dysfunction during T. cruzi infection by releasing or inducing the release of harmful arachidonic acid metabolites such as PGE2 and LTC4 which alter normal cardiac function.
J Mol Cell Cardiol 1992 Jan
PMID:T lymphocytes from T. cruzi-infected mice alter heart contractility: participation of arachidonic acid metabolites. 156 33

This bird's eye view presents connections between the metabolically short-lived local hormones (collectively known as eicosanoids) and atherosclerotic cardiovascular disease. The discussion will be centered around an overview of coronary atherosclerosis with an emphasis on the sequences involved in the formation of atherosclerotic lesions; structure and historical background of oxygenated fatty acids cyclooxygenase and lipoxygenase products--eicosanoids; the generation of free radicals during the formation of endoperoxides by cyclooxygenase; the involvement of eicosanoids in the atherosclerotic inflammatory process, and finally, the effects of non-steroidal and steroidal anti-inflammatory drugs on the synthesis of eicosanoids and experimental atherosclerosis. Little is known about the exact role of eicosanoids in the genesis of atherosclerosis.
Mol Cell Biochem 1992 Apr
PMID:Atherosclerosis: the eicosanoid connection. 158 37

Incubation of rocker-cultured neonatal rat heart cells with 3 mM L(+)-lactate led to a sharp increase in the sensitivity of cardiomyocytes to the beta-adrenergic agonist isoprenaline, as measured by their chronotropic response. This effect was accompanied by a reduction in the arachidonic acid content of the total phospholipids. The phospholipase A2-activator melittin as well as free arachidonic acid induced this supersensitivity to the same degree. On the other hand, the L(+)-lactate-evoked supersensitivity could be blocked by the phospholipase A2 inhibitors mepacrine and n-bromophenacyl-bromide, suggesting an involvement of phospholipase A2 in the process of beta-adrenergic sensitization. The sensitizing action of arachidonic acid was blocked by the lipoxygenase inhibitors esculetin and nordihydroguaiaretic acid, but not by the cyclo-oxygenase inhibitor indomethacin. Supersensitivity was likewise evoked by 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), but not by 5-S-HPETE or 5-S-HETE. These findings suggest that the phospholipase A2-15-lipoxygenase pathway plays a role in the induction of beta-adrenergic supersensitivity in the cultured cardiomyocytes and point to a new physiological role of the lipoxygenase product 15-S-HETE.
Mol Cell Biochem 1991 Mar 27
PMID:Modulation of the beta-adrenergic response in cultured rat heart cells. I. Beta-adrenergic supersensitivity is induced by lactate via a phospholipase A2 and 15-lipoxygenase involving pathway. 164 55


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