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Biomedical subjects

L Iversen

Publications and source records attributed to L Iversen.

At least 73 records · Page 4Linked to original sources
PubMed1994

Identification and subcellular localization of leukotriene A4-hydrolase activity in human epidermis.

The purpose of this study was to determine whether normal human epidermis could produce leukotriene B4 (LTB4) from leukotriene A4 (LTA4) ex vivo, and to localize this LTA4-hydrolase activity. Epidermis obtained by suction blister technique incubated with human polymorphonuclear cells, resulted in a 54% increase in LTB4 formation when compared to polymorphonuclear cells incubated alone. Furthermore, human epidermis transformed exogenous LTA4 into LTB4, and this reaction obeyed Michaelis-Menten kinetics with an apparent Km of 6 microM. Subcellular fractionation of homogenized epidermis localized the LTA4-hydrolase activity mainly in the 105,000 x g supernatant fraction (cytoplasmic fraction). This activity was inhibited by two inhibitors of LTA4-hydrolase (bestatin and captopril). Western blot analysis of the 105,000 x g fraction of homogenized epidermis and cultured keratinocytes supported the presence of a LTA4-hydrolase. Thus, normal human epidermis possesses LTA4-hydrolase activity which can transform exogenous LTA4 and polymorphonuclear cell-derived LTA4 into LTB4. The identification of LTA4-hydrolase in the cytoplasmic fraction of human epidermis indicates that epidermal cells may play a more active role in the enzymatic process leading to formation of the proinflammatory compound LTB4 than previously expected.

Blotting, Western↗
PubMed1994

Changes in metabotropic glutamate receptor mRNA levels following global ischemia: increase of a putative presynaptic subtype (mGluR4) in highly vulnerable rat brain areas.

Metabotropic glutamate receptors mediate their intracellular response by coupling to G proteins and may be divided into three subfamilies: mGluR1 and mGluR5, which stimulate phosphatidylinositol hydrolysis; mGluR2 and mGluR3, which are negatively coupled to cyclic AMP formation; and mGluR4 and mGluR6, which also inhibit forskolin-stimulated cyclic AMP formation. The mGluR4 subtypes may represent L-2-amino-4-phosphonobutyrate-sensitive presynaptic autoreceptors, and two alternatively spliced variants of the mGluR4 coding for two receptors with different C termini have been identified. Using in situ hybridization, we measured the levels of mGluR1-mGluR5 mRNA in regions of the rat brain 24 h after transient global ischemia, a time point when no neuronal damage can yet be observed morphologically. In the hippocampus, the mRNA levels for mGluR1, mGluR2, and mGluR5 were decreased, mGluR3 mRNA levels were unchanged, and the mGluR4 mRNA levels were strongly increased. The strongest increase appeared to be in the mRNA encoding mGluR4b. The mGluR4 mRNA was also increased in the parietal cortex, whereas the ventral posteromedial thalamic nucleus showed a small decrease in its mRNA content. These results suggest that vulnerable neurons react to an increased extracellular glutamate concentration by differential regulation of the mRNA for pre- and postsynaptically located metabotropic glutamate receptors.

Animals↗
PubMed1994

Interleukin-8 secretion and 15-lipoxygenase activity in rheumatoid arthritis: in vitro anti-inflammatory effects by interleukin-4 and interleukin-10, but not by interleukin-1 receptor antagonist protein.

We have examined the ability of interleukin-4 (IL-4), interleukin-10 (IL-10) and interleukin-1 receptor antagonist protein (IL-1ra) to regulate spontaneous interleukin-8 (IL-8) production in cultured SF mononuclear cells (SFMC) from RA. Furthermore, we examined whether IL-4, IL-10, or IL-1ra could influence the production of the arachidonic acid products leukotriene B4 (LTB4), 12-hydroxy-eicosatetraenoic acid (12-HETE) and 15-hydroxy-eicosatetraenoic acid (15-HETE). IL-4 induced a maximal suppression of 75% in the IL-8 secretion in SFMC from 10.0 ng/ml down to 2.5 ng/ml after 24 h and from 17.2 ng/ml to 4.2 ng/ml after 72 h of culture. IL-10 induced a 55% inhibition of the IL-8 secretion at 24 h and a 40% inhibition at 72 h. IL-1ra did not change the spontaneous IL-8 secretion from rheumatoid SFMC. We also examined, whether addition of IL-4, IL-10 or IL-1ra was able to modulate formation of the arachidonic acid products LTB4, 12-HETE and 15-HETE in cultured SF cells, stimulated with the calcium ionophore A23187. 15-HETE was not detected in untreated cultures, nor in IL-10 or IL-1ra treated cultures. IL-4, however, stimulated the formation of the anti-inflammatory mediator; 15-HETE (23 ng/10(6) cells). These results suggest that IL-4 or IL-10, could have beneficial anti-inflammatory effects in RA.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1993

Monohydroxy fatty acids esterified to phospholipids are decreased in lesional psoriatic skin.

Because of the increasing number of reports of the important roles of monohydroxy derivatives of poly-unsaturated fatty acids in the regulation of cell function, we determined the pools of unesterified and esterified monohydroxy fatty acids (MHFAs) in keratomed epidermal slices, taken from lesional and non-lesional psoriatic skin. Extracted phospholipids were separated by thin-layer chromatography. The isolated fractions of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidyl-ethanolamine (PE) were treated with phospholipase A2 to release fatty acids in the sn-2 position. Released MHFAs were separated by reversed-phase and straight-phase high-performance liquid chromatography and identified as the linoleic acid derivatives 9-hydroxy-octadecadienoic acid (9-HODE) and 13-hydroxy-octadecadienoic acid (13-HODE) and as the arachidonic acid derivative 15-hydroxy-eicosatetraenoic acid (15-HETE). These findings are consistent with the presence of unesterified 9-HODE, 13-HODE and 15-HETE. In contrast, 12-hydroxy-eicosatetraenoic acid (12-HETE), although found to be present in high amounts as unesterified 12-HETE, was not detectable in the phospholipids. When compared with non-lesional psoriatic skin, the levels of 9-HODE, 13-HODE and 15-HETE esterified to the sn-2 position of PC, PI and PE in lesional psoriatic skin were significantly decreased (to 28-78% of those in non-lesional skin). This depletion of MHFAs in specific phospholipids may be due to an imbalance between phospholipase and acyltransferase activities. Because the levels of esterified MHFAs may influence signal transduction and eicosanoid metabolism the described changes may be relevant for the inflammatory processes occurring in psoriasis.

Esters↗
PubMed1993

Leukotriene B4 formation during human neutrophil keratinocyte interactions: evidence for transformation of leukotriene A4 by putative keratinocyte leukotriene A4 hydrolase.

In the present study, keratinocytes were coincubated with human neutrophils to determine whether or not an increase in leukotriene B4 formation can occur. Human keratinocytes used were cultured in serum-free, low-calcium medium, whereas neutrophils were purified from heparinized venous blood. After coincubations, formation of leukotriene B4 was determined by reversed-phase high-performance liquid chromatography, coupled with its characteristic UV scan. Confirmation and quantification was by radioimmunoassay. Our data revealed that incubations of keratinocytes (1.5 x 10(6)) alone stimulated with calcium ionophore resulted in no detectable amounts of leukotriene B4. In contrast, incubations of neutrophils (5 x 10(6)) alone resulted in the generation of 62.2 +/- 8.5 ng of LTB4. Coincubations of the neutrophils with keratinocytes (ratio 3:1) resulted in a 56-163% increase in leukotriene B4 formation. To delineate the source of the newly formed leukotriene B4, incubations of keratinocytes with leukotriene A4 revealed that keratinocytes can transform leukotriene A4 into leukotriene B4. These latter findings indicate that although keratinocytes cannot directly metabolize arachidonic acid into leukotriene B4 via the 5-lipoxygenase enzyme, they can transform neutrophil-derived leukotriene A4 into leukotriene B4, thus indicating the possible existence of a putative keratinocyte-leukotriene A4 hydrolase. It is therefore reasonable to speculate that the keratinocytes possess the capacity to generate leukotriene B4 in the epidermis when provided leukotriene A4 and thereby can amplify the inflammatory processes occurring during neutrophil exocytosis. These findings indicate that transcellular metabolism of arachidonic acid metabolites in the epidermis by keratinocytes and neutrophils may contribute to the high levels of leukotriene B4 in lesional skin of inflammatory skin diseases.

Arachidonic Acid↗
PubMed1993

Distribution of monohydroxy fatty acids in specific human epidermal phospholipids.

Monohydroxy derivatives of polyunsaturated fatty acids such as arachidonic acid (AA) and linoleic acid (LA) can modulate inflammation and epidermal proliferation. The purpose of this study was to determine the in vivo distribution of the AA derivatives; 12- and 15-hydroxyeicosatetraenoic acid (12-HETE and 15-HETE) and the LA derivatives; 9- and 13-hydroxyotadecadienoic acid (9-HODE and 13-HODE) in specific phospholipids of normal human skin. Lipids were extracted from 6 normal keratome skin biopsies and phospholipids were separated into the major classes by two-dimensional thin layer chromatography. Monohydroxy fatty acids (MHFAs) released from specific phospholipids after treatment with phospholipase A2 were identified by reversed phase and straight phase high-performance liquid chromatography and UV-absorption spectra. Unesterified MHFAs were determined in a similar way. 9-HODE, 13-HODE and 15-HETE were detectable in phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidylethanolamine (PE). Interestingly, 12-HETE was not detectable in these phospholipids, although the unesterified 12-HETE was detectable in amounts similar to unesterified 15-HETE. Esterified 15-HETE was equally distributed between PI and PC, in which 15-HETE was predominant, accounting for 60% and 69% of the total MHFAs, respectively (p < 0.05). These results demonstrate that the LA derivatives 9-HODE and 13-HODE, as well as the AA derivative 15-HETE, are esterified to PC, PI and PE of normal human epidermis in vivo. The possibility remains that 9-HODE, 13-HODE and 15-HETE, may mediate their biological effects by being incorporated into specific phospholipids.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1993

Modulation of eicosanoid formation by lesional skin of psoriasis: an ex vivo skin model.

The purpose of the present study was to develop an ex vivo skin model to determine the capacity of lesional skin of psoriasis to form leukotriene B4 and other eicosanoids. Keratomed skin samples were incubated in the presence of the calcium ionophore A23187 and arachidonic acid for 45 min at 37 degrees C. After extraction of lipids, eicosanoids were determined by quantitative reversed-phase high-performance liquid chromatography in combination with specific radioimmunoassays. We found that stimulation of skin samples with A23187 and arachidonic acid increased the amount of leukotriene B4 4.0-fold. The 12-lipoxygenase product, 12-hydroxy-eicosatetraenoic acid, and the 15-lipoxygenase product, 15-hydroxy-eicosatetraenoic acid, were both increased 2.7-fold. The cyclooxygenase product, prostaglandin E2, was increased 8.0-fold. Similar incubations using psoriatic scales did not result in formation of eicosanoids. Incubations with the 5-lipoxygenase inhibitor RS43179 inhibited the formation of leukotriene B4 and prostaglandin E2 without significantly affecting the formation of 12-hydroxy-eicosatetraenoic acid and 15-hydroxy-eicosatetraenoic acid. These results reveal that lesional psoriatic skin ex vivo has the enzymatic capacity to increase the levels of eicosanoids. This provides an ex vivo skin model to determine whether putative lipoxygenase inhibitors are able to modulate the formation of eicosanoids in psoriatic skin.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1993

Calcipotriol. A new topical antipsoriatic.

Calcipotriol is a synthetic vitamin D analogue. In vitro it can regulate cell differentiation and proliferation and suppress lymphocyte activities. These actions of calcipotriol at the cellular level are very similar to those of the natural hormone 1,25-(OH)2-D3. In contrast, the systemic effects on calcium and bone metabolism are at least 100 to 200 times less than those of 1,25-(OH)2-D3. Because of this unique pharmacologic profile, calcipotriol has been evaluated for the topical treatment of psoriasis. In well-designed and properly conducted studies involving more than 3000 patients, calcipotriol ointment, 50 micrograms/g, has been shown to be effective and safe for the short- and long-term treatment of psoriasis vulgaris. Calcipotriol ointment should be applied twice daily in amounts up to 100 g/week (Table 1). Used according to these guidelines, calcipotriol treatment does not affect calcium or bone metabolism. Calcipotriol is indicated for the treatment of plaque-type psoriasis vulgaris and has already been approved in several countries. It should be considered a first-line drug for the topical treatment of psoriasis.

Administration, Cutaneous↗
PubMed1992

[Significance of sleeping position on the occurrence of sudden, unexplained infant death. An epidemiological review].

The cause of the sudden infant death syndrome (SIDS) is, according to the definition, unknown. Epidemiological research during recent years has identified a series of probable risk factors. One of these is the use of prone position as sleeping position. In the Western European countries, Australia and New Zealand, a total of 14 case-control studies illustrate a possible connection between the prone position and SIDS. Eleven of the studies revealed a significantly increased relative risk (RR) of between 1.4 and 12.5 for SIDS when using the prone position, while the three remaining studies did not demonstrate increased RR. A meta-analysis of the results of the 14 case-control studies showed an RR of 2.4 for SIDS in the prone position as compared with other sleeping positions. In a single prospective cohort study from Australia, an RR of 3.1 was found for SIDS in the prone position. Interventions in which parents are advised not to place the infants in the prone position during sleep appear to have resulted in considerable reduction in the number of cases of SIDS according to preliminary reports from Great Britain, the Netherlands, Norway and New Zealand. A series of methodological problems can be demonstrated in the published results of these studies, including limited size of study populations, inadequate matching of control groups and absent confounder control. Nevertheless, the total epidemiological evidence, also where Denmark is concerned, speaks in favour of altered recommendations for sleeping positions of infants, particularly because there is no documentation to suggest that the prone position offers any advantages to health.(ABSTRACT TRUNCATED AT 250 WORDS)

Australia↗
PubMed1992

Effect of dihomogammalinolenic acid and its 15-lipoxygenase metabolite on eicosanoid metabolism by human mononuclear leukocytes in vitro: selective inhibition of the 5-lipoxygenase pathway.

The purpose of the present study was to determine the effect of the n-6 fatty acid, dihomogammalinolenic acid (DGLA, 20: 3, n-6) on arachidonic acid (AA) (C20: 4) metabolism by human peripheral mononuclear leukocytes (HPML). After incubation of HPML with A23187 (5 microM) and DGLA, the cyclooxygenase (CO) and lipoxygenase (LO) products were separated and quantified by reversed-phase high-performance liquid chromatography (RP-HPLC) combined with radioimmunoassay. DGLA led to no change in PGE2 formation, but at similar concentrations there was a dose-dependent decrease in LTB4 formation (IC50 = 45.0 microM). The inhibition of LTB4 formation by DGLA was associated with a dose-dependent increase in its 15-LO metabolite 15-hydroxyeicosatraenoic acid (15-HETrE) and its CO metabolite prostaglandin E1 (PGE1). Incubation of HPLM with 15-HETrE (0-1.5 microM) alone did not result in a change in PGE2 formation, whereas 15-HETrE was a much more potent inhibitor of LTB4 formation (IC50 = 0.5 microM) than DGLA. These results show that the addition of DGLA to HPML results in a selective inhibition of LTB4 formation, presumably via its metabolite (15-HETrE).

8,11,14-Eicosatrienoic Acid↗
PubMed1992

Interleukin-8 stimulates the formation of 15-hydroxy-eicosatetraenoic acid by human neutrophils in vitro.

Interleukin-8 (IL-8), is a potent activator of polymorphonuclear leukocyte (PMN) functions including chemotaxis, superoxide anion production, and enzyme release and it is also chemotactic for lymphocytes. Additionally, it has recently been shown that IL-8 stimulates the formation of 5-lipoxygenase (LO) products of arachidonic acid (AA) by human PMNs. The purpose of the present study was to determine whether IL-8 also might affect the formation of 15-LO products from AA. Purified PMNs in phosphate buffered saline were preincubated with and without exogenous AA (10(-5)-10(-4) M) for 10 min. Then IL-8 was added in biologically relevant concentrations ranging from 0.1 to 100 ng/ml and incubation was carried out for 5 min at 37 degrees C. Lipids were then extracted from supernatants, and eicosanoids were determined by quantitative RP-HPLC. Compared with unstimulated cells, IL-8 resulted in a dose dependent increase in both LTB4 and 15-HETE (up to 125% and 40% at 100 ng/ml, respectively). This increase in eicosanoid formation required the presence of exogenous AA. These results indicate that IL-8 is both a potent stimulator of 5-LO activity and of 15-LO activity. LTB4 can induce both inflammation and contribute to hyperproliferation in the skin. 15-HETE in contrast has the ability to inhibit the effects induced by LTB4. Because IL-8 is able to stimulate both LTB4 and 15-HETE formation, the effect of IL-8 as a putative regulator of inflammatory processes may be dependent on the relative stimulation of 5-LO and 15-LO.

Chromatography, High Pressure Liquid↗
PubMed1991

Linoleic acid and dihomogammalinolenic acid inhibit leukotriene B4 formation and stimulate the formation of their 15-lipoxygenase products by human neutrophils in vitro. Evidence of formation of antiinflammatory compounds.

Enzymatic transformation of the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) by the 5-lipoxygenase (LO) enzyme results in the formation of leukotrienes (LTs) including leukotriene B4 (LTB4), which is a potent mediator of inflammation. The purpose of the present study was to determine the effect of other n-6 fatty acids on the formation of LTB4 by human neutrophils and to determine if these n-6 fatty acids themselves may be transformed into products with antiinflammatory capacity. Purified neutrophils isolated from heparinized human venous blood were incubated with A23187 (5 microM) and different concentrations (0-100 microM) of the n-6 fatty acids linoleic acid (LA) and dihomo-gamma-linolenic acid (DGLA). LO products were determined by use of quantitative reversed-phase high performance liquid chromatography (RP-HPLC) and mass spectrometry. The formation of LTB4 was dose dependently inhibited by both LA (IC50 = 45 microM) and DGLA (IC50 = 40 microM). This inhibition of LTB4 formation was associated with a dose dependent increase in the formation of the respective 15-LO products of LA (13-hydroxy-octadecadienoic acid; 13-HODE) and DGLA (15-hydroxy-eicosatrienoic acid; 15-HETrE). To determine whether these 15-LO products themselves might inhibit LTB4 formation, neutrophils were incubated with 13-HODE and 15-HETrE. Both 15-LO products lead to a dose-dependent inhibition of LTB4 formation (IC50 = 7.5 microM and IC50 = 0.2 microM). For comparison the 15-LO product of AA, 15-hydroxy-eicosatetraenoic acid (15-HETE), also inhibited LTB4 formation (IC50 = 0.75 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

8,11,14-Eicosatrienoic Acid↗
PubMed1991

Age and the operationalization of social support.

In most studies social network is operationalized without any consideration of age. But it is to be expected that both the prevalence and the impact on health of the various sources of social support change through life. If this is true, then the use of a global index may lead to distorted results regarding age changes of the social network. In a cross-sectional study of 1500 occupationally active, Danish men aged 16-74, the hypothesized age dependencies were studied with health operationalized as psychological well-being and social support divided into support from wife, children, family and friends. The prevalence of support from the wife increased with age, whereas her impact on health was only significantly positive in the age range 30-49. Support from family and friends was most prevalent among the youngest, but it had a positive impact on health both among the young and the old. The results regarding impact on health are corroborated by two other studies on mortality. These findings point to methodological errors that may distort results when global network measures are used irrespective of the ages of the participants studied.

Adolescent↗