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J A Lindgren

Publications and source records attributed to J A Lindgren.

At least 37 records · Page 2Linked to original sources
PubMed1994

Stimulation of lipoxin synthesis from leukotriene A4 by endogenously formed 12-hydroperoxyeicosatetraenoic acid in activated human platelets.

Human platelets are devoid of 5-lipoxygenase activity but convert exogenous leukotriene A4 (LTA4) either by a specific LTC4 synthase to leukotriene C4 or via a 12-lipoxygenase mediated reaction to lipoxins. Unstimulated platelets mainly produced LTC4, whereas only minor amounts of lipoxins were formed. Platelet activation with thrombin, collagen or ionophore A23187 increased the conversion of LTA4 to lipoxins and decreased the leukotriene production. Maximal effects were observed after incubation with ionophore A23187, which induced synthesis of comparable amounts of lipoxins and cysteinyl leukotrienes (LTC4, LTD4 and LTE4). Chelation of intra- and extracellular calcium with quin-2 and EDTA reversed the ionophore A23187-induced stimulation of lipoxin synthesis from LTA4 and inhibited the formation of 12-hydroxyeicosatetraenoic acid (12-HETE) from endogenous substrate. However, calcium did not affect the 12-lipoxygenase activity in the 100,000 x g supernatant of sonicated platelet suspensions. Furthermore, the stimulatory effect on lipoxin formation induced by platelet agonists could be mimicked in intact platelets by the addition of low concentrations of arachidonic acid, 12-hydroperoxyeicosatetraenoic acid (12-HPETE) or 13-hydroperoxyoctadecadienoic acid (13-HPODE). The results indicate that the elevated lipoxin synthesis during platelet activation is due to stimulated 12-lipoxygenase activity induced by endogenously formed 12-HPETE.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1994

Leukotrienes and lipoxins--new potential performers in the regulation of human myelopoiesis.

Leukotrienes and lipoxins are bioactive lipoxygenase products formed by leukocytes alone or in collaboration with other cells. While the physiological role of lipoxins remains to be clarified, accumulating evidence shows that leukotrienes are important mediators in asthma and inflammation. Consequently, recent clinical trials with leukotriene D4 receptor antagonists and 5-lipoxygenase inhibitors have demonstrated marked reduction of airway symptoms in asthmatic patients. In addition, both leukotrienes and lipoxins have been indicated as modulators of cell proliferation. This article reviews recent findings suggesting that these compounds may also participate in the regulation of human myelopoiesis. Such a role is conceivable since leukotrienes and lipoxins can be produced by bone marrow cells and potently modulate GM-CSF-induced myeloid stem cell proliferation.

Bone Marrow↗
PubMed1994

Population-based mammography screening in Swedish clinical practice: prevalence and incidence screening in Uppsala County.

PURPOSE: To evaluate the results of a population-based mammography screening program in Uppsala County, Sweden, and to compare the findings with those of the randomized Swedish studies. MATERIALS AND METHODS: There were 43,074 women (aged 40-69 years) who were invited to the first screening round. Women aged 40-54 years were examined with two-view mammography, whereas women aged 55-69 years were examined with one-view mammography. During the second screening round, two-view mammography was used to screen dense breasts. RESULTS: The attendance rate was 87% in the first screening round and 78% in the second screening round. The recall rate for further examination was 4.6% in the first round and 5.7% in the second round. On average, five cancers were found per 1,000 women examined in both screening rounds. The rate of advanced breast cancers of stage II or higher decreased statistically significantly from 0.16% in the first screening round to 0.08% in the second screening round (P = .007). CONCLUSION: The results of the Swedish two-county study can be duplicated in clinical practice.

Aged↗
PubMed1993

Stimulation of human myelopoiesis by leukotrienes B4 and C4: interactions with granulocyte-macrophage colony-stimulating factor.

The regulatory role of leukotrienes (LT) on human myelopoiesis was investigated. Mononuclear bone marrow cells from 31 healthy donors were cultivated in the presence of suboptimal concentrations of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for 10 days in semisolid agar. The addition of LTC4 or LTB4 to the cultures dose-dependently stimulated myeloid stem cell proliferation. Maximal effects were observed at 10(-8) mol/L, at which LTC4 induced a 91% +/- 23% (mean +/- SEM; P = .004) and LTB4 a 73% +/- 22% (P = .008) increase in colony formation. In contrast, addition of the LTB4 isomer 5(S), 12(S)-diHETE did not affect the growth. LTD4 exerted a weak potentiating effect on progenitor proliferation (17% +/- 7% growth stimulation at 10(-10) mol/L; P = .034), whereas LTE4 was without consistent effect. Furthermore, LTC4-induced stimulation of colony formation was insensitive to the LTD4 antagonist ICI 198615. The dual lipoxygenase and prostaglandin endoperoxide synthase inhibitor CL42A potently suppressed the proliferation of myeloid colonies, a suppression that could be reversed by parallel addition of LTB4 or LTC4. The results suggest that both LTB4 and LTC4 possess strong and specific synergistic stimulatory effects on GM-CSF-induced human myeloid progenitor cell growth.

Bone Marrow↗
PubMed1992

Conversion of 5,6-dihydroxyeicosatetraenoic acids. A novel pathway for lipoxin formation by human platelets.

Leukotriene A4 may be metabolized to 5(S),6(R)- and 5(S),6(S)-dihydroxy-7,9-trans-11,14-cis-eicosatetraenoic acids by enzymatic or non-enzymatic hydrolysis. Incubation of human platelet suspensions with these dihydroxy acids led to the formation of lipoxin A4 and 6(S)-lipoxin A4 via lipoxygenation at C-15. Furthermore, human platelets converted the two 5(R),6(S)- and 5(R),6(R)-dihydroxy-7,9-trans-11,14-cis-eicosatetraenoic acids to tetraene-containing trihydroxyeicosatetraenoic acids. In contrast, leukotrienes C4, D4 and E4 were not transformed to cysteinyl-lipoxins. Time-course studies of leukotriene A4 metabolism in human platelet suspensions indicated lipoxin formation via two pathways: (i) direct conversion of leukotriene A4, leading to formation of the lipoxin intermediate 15-hydroxy-leukotriene A4; and (ii) 15-lipoxygenation of the 5(S),6(R)- and 5(S),6(S)-dihydroxyeicosatetraenoic acids. The results demonstrate that lipoxygenation at C-15 of 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acids may be an alternative novel pathway for platelet-dependent lipoxin formation.

Blood Platelets↗
PubMed1992

Production of 12-hydroxyeicosatetraenoic acid in early pregnant uterine cervix--lack of correlation to mifepristone-induced cervical ripening. A double-blind randomized biomechanical and biochemical study.

The regulation of cervical ripening in pregnancy may involve arachidonic acid metabolites. We studied the formation of lipoxygenase products in cervical biopsies from twenty nulliparous women requesting a first trimester abortion. The patients were randomly allocated to receive either 100 mg of the progesterone antagonist mifepristone (RU 486) or placebo 48 and 36 hours before surgery. A capacity to produce significant amounts of 12-HETE and material co-chromatographing with leukotrienes was observed in the cervical tissue. No qualitative or quantitative relationship to mifepristone-induced cervical ripening was found. Although our data suggest a large variation of 12-HETE production it remains to clarify its role in the cervix.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia.

The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

Formation and proliferative effects of lipoxins in human bone marrow.

Lipoxins A4 and B4 together with the all-trans lipoxin (LX) isomers were produced by normal human bone marrow cell suspensions after incubation with ionophore A23187. Both LXA4 and LXB4 enhanced the growth of myeloid progenitor cells in semisolid agar in the presence of suboptimal concentrations of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Lipoxin A4 at 10(-10) M stimulated the colony formation in 13 out of 15 tested human bone marrows with a mean (+/- SEM) increase of 47 +/- 11% (p = 0.001). A similar stimulatory effect was observed after addition of LXB4 (10(-10) M). The monohydroxyeicosatetraenoic acids 5-, 12- and 15-HETE did not affect colony growth. In addition, LXA4 (10(-8) M) efficiently counteracted the increased colony formation induced by leukotriene C4 (10(-10) M), suggesting an antagonistic relationship between these lipoxygenase products. The results support a role for lipoxins in the regulation of human myelopoiesis.

Bone Marrow↗
PubMed1991

On the mechanism of transcellular lipoxin formation in human platelets and granulocytes.

Endogenous arachidonic acid was converted to lipoxins A4, B4 and (6S)-lipoxin A4, in ionophore-A23187-stimulated mixtures of human platelets and granulocytes, while no lipoxins were formed when these cells were incubated separately. However, pure platelet suspensions transformed exogenous leukotriene A4 to lipoxins, including lipoxin A4 and (6S)-lipoxin A4, but not lipoxin B4. This compound was produced exclusively in the presence of granulocytes. A common unstable tetraene intermediate in lipoxin formation, 15-hydroxy-leukotriene A4 [5(6)-epoxy-15-hydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid], was indicated by trapping experiments with methanol. Thus, identical profiles of less polar tetraene-containing derivatives were formed from leukotriene A4 in platelet suspensions, from exogenous 15-hydroxyeicosatetraenoic acid in granulocyte suspensions and from endogenous substrate in mixed platelet/granulocyte suspensions. Evidence for the involvement of 12-lipoxygenase in platelet-dependent lipoxin formation was obtained. Thus, lipoxin synthesis from leukotriene A4 and 12-hydroxyeicosatetraenoic acid production from arachidonic acid by human platelets was equally inhibited by 15-hydroxyeicosatetraenoic acid with 50% inhibition obtained at 7.0 microM and 8.2 microM, respectively. In experiments with subcellular preparations from platelets, lipoxin synthesis was observed in both the particulate and soluble fraction and was paralleled by the 12-lipoxygenase activity. Furthermore, lipoxin formation from leukotriene A4 in platelet sonicates was dose-dependently inhibited by exogenous arachidonic acid. Finally, 12-lipoxygenase-deficient platelets from a patient with chronic myelogenous leukemia were totally unable to produce lipoxins from exogenous or granulocyte-derived leukotriene A4. It is concluded that the transcellular lipoxin synthesis is dependent on the platelet 12-lipoxygenase and proceeds via the unstable intermediate, 15-hydroxy-leukotriene A4. This tetraene epoxide is transformed to lipoxin B4 by a granulocyte epoxide hydrolase activity or to lipoxin A4 and lipoxins A4/B4 isomers by enzymatic or nonenzymatic hydrolysis.

Arachidonic Acids↗
PubMed1991

On the mechanism of induction of DNA synthesis in cultured arterial smooth muscle cells by leukotrienes. Possible role of prostaglandin endoperoxide synthase products and platelet-derived growth factor.

The induction of DNA replication in rat aortic smooth muscle cells (SMCs) by leukotrienes (LTs) was studied in order to elucidate the mechanisms of action in further detail. The effect of LTB4 was blocked by the prostaglandin (PG) synthesis inhibitor indomethacin and the effects of LTC4 and LTD4 were blocked by the cysteinyl-containing leukotriene receptor antagonists FPL 55712 and ICI 198615. These observations suggest that LTB4 and the cysteinyl-containing leukotrienes act via distinct receptors and point to a role for prostaglandin endoperoxide synthase products in bringing about the effect of LTB4. Radioimmunological determinations and analyses of [3H]arachidonic acid metabolism showed that the SMCs were able to synthesize PGI2 (measured as the stable metabolite 6-keto-PGF1 alpha), PGE2, PGF2 alpha and 15(S)hydroxy-eicosatetraenoic acid (15(S)HETE). Moreover, picomolar concentrations of arachidonic acid, PGI2, PGE2, PGF2 alpha and 15(S)HETE induced DNA replication in the SMCs under serum-free conditions, whereas linoleic acid, 6-keto-PGF1 alpha and 5(S)HETE were inactive in this respect. Analysis of conditioned media for mitogenic activity (with or without antibodies against platelet-derived growth factor, PDGF) and for the presence of material competing with radioiodinated PDGF for binding to specific cell surface receptors indicated that LTB4 stimulated release of PDGF or a PDGF-like molecule from the cells. These findings suggest that the growth-promoting effect of LTB4 is mediated via a prostaglandin endoperoxide synthase product and/or PDGF produced by the cells themselves.

Animals↗
PubMed1990

Lipoxin formation in human nasal polyps and bronchial tissue.

Chopped human nasal polyps and bronchial tissue produced lipoxin A4 and isomers of lipoxins A4 and B4, but not lipoxin B4, after incubation with exogenous leukotriene A4. In addition, these tissues transformed arachidonic acid to 15-hydroxyeicosatetraenoic acid. The capacity per gram of tissue to produce lipoxins and 15-hydroxyeicosatetraenoic acid was 3-5-times higher in the nasal polyps. Neither tissue produced detectable levels of lipoxins or leukotrienes after incubation with ionophore A23187 and arachidonic acid. Co-incubation of nasal polyps and polymorphonuclear granulocytes with ionophore A23187 led to the formation of lipoxins, including lipoxins A4 and B4. The results indicate the involvement of an epithelial 15-lipoxygenase in lipoxin formation in human airways.

Arachidonate 15-Lipoxygenase↗
PubMed1990

Elevated white blood cell synthesis of leukotriene C4 in chronic myelogenous leukaemia but not in polycythaemia vera.

Leukotriene (LT) formation was studied in ionophore A23187-stimulated white blood cell (WBC) preparations from patients with chronic myelogenous leukaemia (CML; n = 14), polycythaemia vera (PV; n = 10) and two control groups consisting of patients with non-malignant inflammatory disease (n = 4) and normal healthy donors (n = 25). The synthesized products were identified and quantitated using high-performance liquid chromatography combined with computerized UV-spectroscopy. White blood cell preparations from the CML patients produced more LTC4 (40.2 +/- 7.9 pmol/10(6) WBC, mean +/- SEM) than WBC from the healthy donors (9.0 +/- 1.8), P less than 0.0005. In contrast, the formation of LTB4 was normal and there was no increase in the total leukotriene synthesis (the sum of LTC4, LTB4, 20-OH-LTB4 and the delta 6-trans-isomers of LTB4). The ratio between leukotrienes C4 and B4 was strongly elevated in the CML group; 1.67 +/- 0.25 v. 0.37 +/- 0.07 in the controls, P less than 0.0005. No significant correlation was observed between the levels of LTC4 and the number of known LTC4 producing cells (such as monocytes, eosinophils and basophils) in the CML WBC preparations. In contrast, a correlation was found between the sum of neutrophilic granulocytes and metamyelocytes in these suspensions and the amount of LTB4 formed; r = 0.600, P less than 0.05. A number of other laboratory or clinical variables of the CML patients (including total white blood cell and platelet counts, differential counts, previous cytotoxic treatment, time from diagnosis, time from last treatment, post study survival and age) did not significantly correlate with the formation of leukotrienes. No abnormality in the production of LTB4 or LTC4 was observed in granulocyte and WBC preparations from the patients with polycythaemia vera and non-malignant inflammatory disease, respectively. The results indicate a selectively increased LTC4 producing capacity in CML.

Adult↗