Metabolism of leukotriene B4 by polymorphonuclear granulocytes of severely burned patients

Brom, J.; König, Wolfgang; Köller, Manfred; Groß-Weege, W.; Erbs, G; Müller, F. E.

doi:10.1016/0262-1746(87)90072-2

Cited by 27 publications

(18 citation statements)

References 12 publications

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“…In contrast, some clinical trials involving LTB 4 modulators reported pulmonary infections as severe adverse events indicating that in humans, LTB 4 should not be regarded as a pro‐inflammatory effector but rather as a booster of innate immunity and host defense. Of note, the ω‐LTB 4 /LTB 4 ratio is increased in neutrophils purified from the blood of cystic fibrosis patients and from severely burned patients, two conditions in which infections are not well controlled. Furthermore, 20‐OH‐LTB 4 and 20‐COOH‐LTB 4 were detected in the sputum of patients with cystic fibrosis in larger amount than LTB 4 itself (55% 20‐COOH‐LTB 4 :20% 20‐OH‐LTB 4 :25% LTB 4 ) .…”

Section: Discussionmentioning

confidence: 99%

20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4-mediated responses of human neutrophils and eosinophils

Archambault

Poirier

Lefebvre

et al. 2019

Journal of Leukocyte Biology

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Leukotriene B4 (LTB4) plays a prominent role in innate immunity as it induces phagocyte recruitment, the release of antimicrobial effectors, and as it potentiates the ingestion and killing of pathogens. In humans, LTB4 has a short half‐life and is rapidly metabolized by leukocytes, notably into 20‐OH‐ and 20‐COOH‐LTB4 by neutrophils. Although these LTB4 metabolites bind to the BLT1 receptor with high affinity, they activate neutrophils to a much lower extent than LTB4. We thus postulated that LTB4 metabolites could dampen BLT1‐mediated responses, therefore limiting the impact of LTB4 on human neutrophil functions. We found that 20‐OH‐LTB4 and 20‐COOH‐LTB4 inhibited all of the LTB4‐mediated neutrophil responses we tested (migration, degranulation, leukotriene biosynthesis). The potencies of the different compounds at inhibiting LTB4‐mediated responses were 20‐OH‐LTB4 = CP 105,696 (BLT1 antagonist) > > 20‐COOH‐LTB4 ≥ resolvin E1 (RVE1). In contrast, the fMLP‐ and IL‐8‐mediated responses we tested were not affected by the LTB4 metabolites or RVE1. 20‐OH‐LTB4 and 20‐COOH‐LTB4 also inhibited the LTB4‐mediated migration of human eosinophils but not that induced by 5‐KETE. Moreover, using 20‐COOH‐LTB4, LTB4, and LTB4‐alkyne, we show that LTB4 is a chemotactic, rather than a chemokinetic factor for both human neutrophils and eosinophils. In conclusion, our data indicate that LTB4 metabolites and RVE1 act as natural inhibitors of LTB4‐mediated responses. Thus, preventing LTB4 ω‐oxidation might result in increased innate immunity and granulocyte functions.

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Section: Discussionmentioning

confidence: 99%

20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4-mediated responses of human neutrophils and eosinophils

Archambault

Poirier

Lefebvre

et al. 2019

Journal of Leukocyte Biology

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“…LTC4, LTD4 and LTE4 participate in the local inflammatory reac tion by increasing bronchomotor tone, epithelial secretion and vasopermeability. According to the enzymatic subset, eosinophils have a high capacity to produce predominantly LTC4, whereas neutrophil granulocytes produce LTB4; moreover, neutrophils metabolize LTB4 into co-oxidated products [13][14][15] thus counteracting the biological effect of the mole cule. In addition, granulocytes and platelets synthe size monohydroxylated unsaturated fatty acids (mono-HETEs), such as 5-, 12-, and 15-HETE, which have chemotactic, proliferative, as well as bronchoconstrictory effects [ 16].…”

Section: Introductionmentioning

confidence: 99%

Generation and Metabolism of Leukotrienes in Granulocytes of Patients with Cystic Fibrosis

Saak

Schönfeld

Knöller

et al. 1990

Int Arch Allergy Immunol

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We studied the generation and metabolism of lipoxygenase products in peripheral granulocytes from children suffering from cystic fibrosis (CF). Peripheral granulocytes were stimulated at different times (days) before and during anti-infectious treatment with the Ca ionophore (7.5 μM, 5 and 20 min), opsonized zymosan (2 mg) and arachidonic acid (50 μM); the amount of lipoxygenase products in the cell supernatants was determined by high performance liquid chromatography. Granulocytes from patients with CF, compared to an age-matched control group, showed an increased ω-oxidation of the synthesized leukotriene (LTB₄) into 20-OH- and 20-COOH-LTB₄ after stimulation with the Ca ionophore (ratio of LTB₄ versus ω-oxidated products in patients with CF: 0.77 ± 0.07, mean ± SEM, n = 11; control group: 1.07 ± 0.1, n = 11, p < 0.01) whereas the combined amounts of LTB₄ and its ω-oxidated products did not differ significantly. A comparable profile was observed with opsonized zymosan. Stimulation of the cells with the Ca ionophore combined with arachidonic acid led to a significantly increased formation of lipoxygenase products in the patient group, whereas only a slight enhancement was observed in the control group. During the 14-day anti-infectious treatment a normalization of the altered pattern was observed. 12-Hydroxyeicosatetraenoic acid (12-HETE) production from platelets within the granulocyte fraction was significantly depressed in the CF group compared to the controls (38.5 ± 12.5 versus 339 ± 93 ng/5 ± 10⁶ cells, p < 0.005). Within the CF group a strong correlation between the release of LTB₄ and its metabolites, the production of 12-HETE and clinical (e.g. pO₂, FEV₁) and laboratory findings (e.g. IgE and IgG levels, C-reactive protein) was established. Our data suggest that the inflammatory process in patients with CF is associated with an alteration of the lipoxygenase pathway of granulocytes which correlates with the clinical signs of inflammation.

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“…HPLC analysis was performed using a Nucleosil 5C18 column (4 x 250 mm) with metha-nol: water:phosphoric acid (57:43:0.05; pH 5.4) as mobile phase. The flow was adjusted to 1 ml/min and the leukotrienes were detected at 272 nm using an UV detector [8].…”

Section: Analysis Of Leukotriene Releasementioning

confidence: 99%

Modulation of leukotriene metabolism from human polymorphonuclear granulocytes by bifonazole

Bremm

Plempel

1991

Mycoses

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Summary. The influence of bifonazole and other azoles on the leukotriene‐metabolism of human neu‐trophil granulocytes (PMN) was investigated. The cells were stimulated with the Ca‐ionophore A23187 over 15 minutes in the presence of the azoles. Subsequently the supernatants were analyzed for their leukotriene content by reversed‐phase HPLC. In order to confirm that the observed effects are not due to cytotoxic phenomena tests were performed to evaluate the viability of the granulocytes. The chemotactic active leukotriene B4 (LTB4) and its inactive omega‐metabolites were detected and quantified by HPLC analysis. The results clearly demonstrated that bifonazole inhibited the omega‐oxidation already at concentrations as low as 0.5 μg ml‐1. As a consequence the LTB4‐level became elevated. At concentrations up to 64 μg ml‐1 bifonazole totally blocked the formation of leukotrienes in human granulocytes. Identical experiments were performed with other azoles and with various anti‐inflammatory drugs just to have a comparison with bifonazole. It is evident that bifonazole in addition to its well known antimycotic action shows a unique modulation of the leukotriene‐metabolism, which is important for its anti‐inflammatory potency. Zusammenfassung. Es wurde der Einfluß von Bifonazol und anderer Azole auf den Leukotrien‐Me‐tabolismus neutrophiler Granulozyten des Menschen (PMN) untersucht. Die Zellen wurden mit dem Ca‐Ionophor A23187 15 min lang in Gegenwart der Azole stimuliert. Danach wurde der Überstand in der Reverse‐Phase‐HPLC auf den Leuko‐trien‐Gehalt untersucht. Um sicherzustellen, daß die beobachteten Effekte nicht auf zytotoxischen Phänomenen beruhen, wurde die Lebensfähigkeit der Granulozyten geprüft. Das chemotaktisch aktive Leukotrien B4 (LTB4) und seine inaktiven Ome‐ga‐Metabolite wurden quantitativ mittels HPLC erfaßt. Die Ergebnisse belegen, daß Bifonazol bereits in Konzentrationen von 0,5 μg ml‐1 die Omega‐Oxidation hemmt. Infolgedessen erhöhte sich der LTB4‐Spiegel. In Konzentrationen bis zu 64 μg ml‐1 blockierte Bifonazol die Leukotrien‐Bildung in menschlichen Granulozyten völlig. Identische Experimente wurden mit anderen Azolen und verschiedenen antientzündlichen Substanzen zum Vergleich mit Bifonazol durchgeführt. Offensichtlich bewirkt Bifonazol über seine bekannte antimykoti‐sche Aktivität hinaus eine einzigartige Modulation des Leukotrien‐Metabolismus, die ihm antientzündliche Eigenschaften verleiht.

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Metabolism of leukotriene B4 by polymorphonuclear granulocytes of severely burned patients

Cited by 27 publications

References 12 publications

20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4-mediated responses of human neutrophils and eosinophils

20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4-mediated responses of human neutrophils and eosinophils

Generation and Metabolism of Leukotrienes in Granulocytes of Patients with Cystic Fibrosis

Modulation of leukotriene metabolism from human polymorphonuclear granulocytes by bifonazole

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