The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury

I. S. Farrukh, J. R. Michael, S. P. Peters, A. M. Sciuto, N Franklin Adkinson, H. S. Freeland, A. Paky, Ernst W Spannhake, W. R. Summer, G. H. Gurtner

Research output: Contribution to journalArticle

Abstract

Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compare an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 μM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 μM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 μM). To produce lung injury, t-bu-OOH (300 μM) was infused throughout the first minute of 4 successive 10-min periods. Indomethacin, ETYA, and FPL 55712 each blocked the increase in pulmonary arterial pressure caused by t-bu-OOH. Despite similar pulmonary arterial pressures in the 3 treatment groups, indomethacin only partially reduced the gain in lung weight caused by t-bu-OOH, whereas treatment with ETYA or FPL 55712 prevented the gain in lung weight. Either ETYA or FPL 55712 produced a significantly greater protection against edema formation than did treatment with indomethacin (p <0.01). In separate experiments, we studied the effect of indomethacin, ETYA, and FPL 55712 on the increased pulmonary synthesis of thromboxane, prostacyclin, and the peptide leukotrienes caused by t-bu-OOH infusion. Indomethacin prevented the synthesis of cyclooxygenase products, but did not alter the increased synthesis of the peptide leukotrienes. ETYA inhibited the augmented synthesis of thromboxane, prostacyclin, and the peptide leukotrienes, whereas FPL 55712 did not prevent the synthesis of these arachidonic acid metabolites. We also tested the possibility that ETYA, indomethacin, or FPL 55712 might reduce the production of oxygen-free radicals. Indomethacin ETYA, and FPL 55712 did not reduce the in vitro production of superoxide anion and singlet oxygen. Our results indicate that infusion of the lipid peroxide t-bu-OOH stimulates the synthesis of both cyclooxygenase and lipoxygenase products of arachidonic acid, and that cyclooxygenase-derived products cause the pulmonary vasoconstriction, whereas lipoxygenase-derived products appear to be responsible for the increase in vascular permeability.

Original languageEnglish (US)
Pages (from-to)1343-1349
Number of pages7
JournalAmerican Review of Respiratory Disease
Volume137
Issue number6
StatePublished - 1988

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Lipoxygenase
Lung Injury
Prostaglandin-Endoperoxide Synthases
Oxidants
Indomethacin
Lung
Arachidonic Acid
Acids
Leukotrienes
Thromboxanes
Capillary Permeability
Epoprostenol
Lipid Peroxides
Vasoconstriction
Peptides
Arterial Pressure
5,8,11,14-Eicosatetraynoic Acid
Leukotriene Receptors
Leukotriene Antagonists
tert-Butylhydroperoxide

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Farrukh, I. S., Michael, J. R., Peters, S. P., Sciuto, A. M., Adkinson, N. F., Freeland, H. S., ... Gurtner, G. H. (1988). The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury. American Review of Respiratory Disease, 137(6), 1343-1349.

The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury. / Farrukh, I. S.; Michael, J. R.; Peters, S. P.; Sciuto, A. M.; Adkinson, N Franklin; Freeland, H. S.; Paky, A.; Spannhake, Ernst W; Summer, W. R.; Gurtner, G. H.

In: American Review of Respiratory Disease, Vol. 137, No. 6, 1988, p. 1343-1349.

Research output: Contribution to journalArticle

Farrukh, IS, Michael, JR, Peters, SP, Sciuto, AM, Adkinson, NF, Freeland, HS, Paky, A, Spannhake, EW, Summer, WR & Gurtner, GH 1988, 'The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury', American Review of Respiratory Disease, vol. 137, no. 6, pp. 1343-1349.
Farrukh IS, Michael JR, Peters SP, Sciuto AM, Adkinson NF, Freeland HS et al. The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury. American Review of Respiratory Disease. 1988;137(6):1343-1349.
Farrukh, I. S. ; Michael, J. R. ; Peters, S. P. ; Sciuto, A. M. ; Adkinson, N Franklin ; Freeland, H. S. ; Paky, A. ; Spannhake, Ernst W ; Summer, W. R. ; Gurtner, G. H. / The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury. In: American Review of Respiratory Disease. 1988 ; Vol. 137, No. 6. pp. 1343-1349.
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abstract = "Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compare an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 μM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 μM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 μM). To produce lung injury, t-bu-OOH (300 μM) was infused throughout the first minute of 4 successive 10-min periods. Indomethacin, ETYA, and FPL 55712 each blocked the increase in pulmonary arterial pressure caused by t-bu-OOH. Despite similar pulmonary arterial pressures in the 3 treatment groups, indomethacin only partially reduced the gain in lung weight caused by t-bu-OOH, whereas treatment with ETYA or FPL 55712 prevented the gain in lung weight. Either ETYA or FPL 55712 produced a significantly greater protection against edema formation than did treatment with indomethacin (p <0.01). In separate experiments, we studied the effect of indomethacin, ETYA, and FPL 55712 on the increased pulmonary synthesis of thromboxane, prostacyclin, and the peptide leukotrienes caused by t-bu-OOH infusion. Indomethacin prevented the synthesis of cyclooxygenase products, but did not alter the increased synthesis of the peptide leukotrienes. ETYA inhibited the augmented synthesis of thromboxane, prostacyclin, and the peptide leukotrienes, whereas FPL 55712 did not prevent the synthesis of these arachidonic acid metabolites. We also tested the possibility that ETYA, indomethacin, or FPL 55712 might reduce the production of oxygen-free radicals. Indomethacin ETYA, and FPL 55712 did not reduce the in vitro production of superoxide anion and singlet oxygen. Our results indicate that infusion of the lipid peroxide t-bu-OOH stimulates the synthesis of both cyclooxygenase and lipoxygenase products of arachidonic acid, and that cyclooxygenase-derived products cause the pulmonary vasoconstriction, whereas lipoxygenase-derived products appear to be responsible for the increase in vascular permeability.",
author = "Farrukh, {I. S.} and Michael, {J. R.} and Peters, {S. P.} and Sciuto, {A. M.} and Adkinson, {N Franklin} and Freeland, {H. S.} and A. Paky and Spannhake, {Ernst W} and Summer, {W. R.} and Gurtner, {G. H.}",
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T1 - The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury

AU - Farrukh, I. S.

AU - Michael, J. R.

AU - Peters, S. P.

AU - Sciuto, A. M.

AU - Adkinson, N Franklin

AU - Freeland, H. S.

AU - Paky, A.

AU - Spannhake, Ernst W

AU - Summer, W. R.

AU - Gurtner, G. H.

PY - 1988

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N2 - Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compare an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 μM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 μM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 μM). To produce lung injury, t-bu-OOH (300 μM) was infused throughout the first minute of 4 successive 10-min periods. Indomethacin, ETYA, and FPL 55712 each blocked the increase in pulmonary arterial pressure caused by t-bu-OOH. Despite similar pulmonary arterial pressures in the 3 treatment groups, indomethacin only partially reduced the gain in lung weight caused by t-bu-OOH, whereas treatment with ETYA or FPL 55712 prevented the gain in lung weight. Either ETYA or FPL 55712 produced a significantly greater protection against edema formation than did treatment with indomethacin (p <0.01). In separate experiments, we studied the effect of indomethacin, ETYA, and FPL 55712 on the increased pulmonary synthesis of thromboxane, prostacyclin, and the peptide leukotrienes caused by t-bu-OOH infusion. Indomethacin prevented the synthesis of cyclooxygenase products, but did not alter the increased synthesis of the peptide leukotrienes. ETYA inhibited the augmented synthesis of thromboxane, prostacyclin, and the peptide leukotrienes, whereas FPL 55712 did not prevent the synthesis of these arachidonic acid metabolites. We also tested the possibility that ETYA, indomethacin, or FPL 55712 might reduce the production of oxygen-free radicals. Indomethacin ETYA, and FPL 55712 did not reduce the in vitro production of superoxide anion and singlet oxygen. Our results indicate that infusion of the lipid peroxide t-bu-OOH stimulates the synthesis of both cyclooxygenase and lipoxygenase products of arachidonic acid, and that cyclooxygenase-derived products cause the pulmonary vasoconstriction, whereas lipoxygenase-derived products appear to be responsible for the increase in vascular permeability.

AB - Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compare an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 μM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 μM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 μM). To produce lung injury, t-bu-OOH (300 μM) was infused throughout the first minute of 4 successive 10-min periods. Indomethacin, ETYA, and FPL 55712 each blocked the increase in pulmonary arterial pressure caused by t-bu-OOH. Despite similar pulmonary arterial pressures in the 3 treatment groups, indomethacin only partially reduced the gain in lung weight caused by t-bu-OOH, whereas treatment with ETYA or FPL 55712 prevented the gain in lung weight. Either ETYA or FPL 55712 produced a significantly greater protection against edema formation than did treatment with indomethacin (p <0.01). In separate experiments, we studied the effect of indomethacin, ETYA, and FPL 55712 on the increased pulmonary synthesis of thromboxane, prostacyclin, and the peptide leukotrienes caused by t-bu-OOH infusion. Indomethacin prevented the synthesis of cyclooxygenase products, but did not alter the increased synthesis of the peptide leukotrienes. ETYA inhibited the augmented synthesis of thromboxane, prostacyclin, and the peptide leukotrienes, whereas FPL 55712 did not prevent the synthesis of these arachidonic acid metabolites. We also tested the possibility that ETYA, indomethacin, or FPL 55712 might reduce the production of oxygen-free radicals. Indomethacin ETYA, and FPL 55712 did not reduce the in vitro production of superoxide anion and singlet oxygen. Our results indicate that infusion of the lipid peroxide t-bu-OOH stimulates the synthesis of both cyclooxygenase and lipoxygenase products of arachidonic acid, and that cyclooxygenase-derived products cause the pulmonary vasoconstriction, whereas lipoxygenase-derived products appear to be responsible for the increase in vascular permeability.

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