Biogenesis of chemotactic molecules by the arachidonate lipoxygenase system of platelets

Inflammation of the guinea‐pig colon was produced by skin sensitization and subsequent intracolonic challenge with the chemical hapten, dinitrochlorobenzene. Metabolism of [14C]‐arachidonic acid by homogenates of control colon was very low, although metabolites co‐migrating on thin layer chromatography (t.l.c.) with prostaglandin E2 (PGE2), PGF2α, PGD2, 6‐keto‐PGF1α, thromboxane B2 (TXB2), HHT and 11‐, 12‐, 15‐HETE were formed. There was an overall 3 fold increase in metabolism of [14C]‐arachidonic acid by homogenates of inflamed mucosa. The greatest increase in metabolite formation was of PGE2, with smaller increases in HHT, 11‐, 12‐, 15‐HETE, PGD2, TXB2, PGF2α and 6‐keto‐PGF1α. The formation of these metabolites was inhibited both by indomethacin and the dual pathway inhibitor, BW755C. The formation of immunoreactive PGE2, TXB2 and 6‐keto‐PGF1α was also increased in homogenates of inflamed guinea‐pig colon. The small level of immunoreactive LTB4 detected in control colon was not changed in inflamed colonic tissue. The dinitrochlorobenzene model of colitis offers a means of studying arachidonic acid metabolism in an immune‐mediated inflammatory response in intestinal tissue.

Section: Discussionmentioning

confidence: 99%

Increased metabolism of arachidonic acid in an immune model of colitis in guinea‐pigs

Boughton‐Smith

Whittle

1985

“…An inhibition by steroids of phosphatide catabolism in vivo could well contribute to their anti-inflammatory effect since it would limit the supply of substrate to the cyclo-oxygenase as well as the lipoxygenase which generates HETE, shown by Turner, Tainer & Lynn (1975) to be strongly chemotactic for polymorphonuclear leucocytes. In addition to the formation of potentially toxic products of phosphatide metabolism such as lysolecithin and lipid peroxides would also be reduced.…”

Section: Discussionmentioning

confidence: 99%

PHOSPHOLIPASE A₂ ACTIVITY OF GUINEA‐PIG ISOLATED PERFUSED LUNGS: STIMULATION, AND INHIBITION BY ANTI‐INFLAMMATORY STEROIDS

Blackwell

Flower

Nijkamp

et al. 1978

303

1 A simple double-isotope assay for phospholipase A2 activity of perfused organs is described. 2 Guinea-pig lungs perfused through the pulmonary circulation exhibit a low background enzyme activity. This activity is blocked by dexamethasone, betamethasone and hydrocortisone, mepacrine, procaine or chlorpromazine. Aspirin and indomethacin are without effect. 3 Mechanical trauma, antigen challenge or injections of bradykinin, rabbit aorta contracting substance-releasing factor (RCS-RF) or histamine increase 'basal' phospholipase activity. The effect of these agents, except that of bradykinin, is blocked by dexamethasone or mepacrine. 4 The blocking effect of steroids is cumulative and dose-dependent. They do not work in cell-free systems. Inhibition by mepacrine is rapid and is effective in cell-free lung homogenates. 5 It is suggested that agents which liberate prostaglandin endoperoxides and thromboxane A2 from perfused lungs do so by activating phospholipase A2.

“…However, recent reports indicate that lipoxygenase products of arachidonic acid metabolism could be involved in leukocyte migration. Some mono-hydroxy acids are chemotactic for polymorphonuclear leukocytes (PMNs) in vitro (Turner, Tainer & Lynn, 1975;Goetzl & Sun, 1979) and it has recently been shown that LTB4 is one of the most potent endogenous chemotactic factors known (Ford-Hutchinson, Bray, Doig, Shipley & Smith, 1980;Palmer, Stepney, Higgs & Eakins, 1980).…”

Section: Introductionmentioning

confidence: 99%

The Inflammatory Effects of Hydroperoxy and Hydroxy Acid Products of Arachidonate Lipoxygenase in Rabbit Skin

Higgs

Salmon

Spayne

1981

113

1 The inflammatory effects of hydroperoxy (HPETE) and hydroxy (HETE) acids, synthesized by arachidonic acid lipoxygenases, have been investigated in rabbit skin.2 High doses (10-20pg) of 5-, 12-or 15-HPETE or the 5,12-di-hydroxy acid, leukotriene B4 (0.1-1 fg), caused small but significant increases in plasma exudation following intra-dermal injection.3 Leukotriene B4 was equipotent with prostaglandin E2 and prostacyclin in potentiating bradykinin-induced plasma exudation, and was 100 times more active in this property than any other lipoxygenase product tested. 4 Leukotriene B4-induced plasma exudation was enhanced by prostaglandin E2. 5 The mono-HETEs were relatively inactive in causing or enhancing plasma exudation.6 Leukotriene B4 (0.1 fg) or prostaglandin El (1.0 pg) significantly elevated leukocyte accumulation in rabbit skin, whereas PGE2, 5-HPETE, 5-HETE, 12-HPETE or 12-HETE were inactive at doses up to 1 pg.