Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation

McAdam, Brendan; Mardini, Issam A.; Habib, Aı̈da; Burke, Anne; Lawson, John A.; Kapoor, Shiv; FitzGerald, Garret A.

doi:10.1172/jci9523

Cited by 211 publications

(168 citation statements)

References 78 publications

(70 reference statements)

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“…Expression of human COX-2 is very specific in certain tissues at basal level, and it is widely expressed in human endothelium (40) and human brain (41). During its absorption and distribution, orally taken aspirin can interact and acetylate endothelial COX-2, blocking prostacyclin biosynthesis (42,43). Considering the large surface area of the human vasculature (~1,000 m 2 ; whole body estimate) (44), the EPA present in blood can be in contact with endothelial cells and converted to 18S-HEPE by acetylated COX-2 for further biosynthesis to 18S E-series resolvins via transcellular mechanisms with leukocytes (19,45).…”

Section: Figurementioning

confidence: 99%

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Pillai²,

Recchiuti³

et al. 2011

J. Clin. Invest.

254

305

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E-series resolvins are antiinflammatory and pro-resolving lipid mediators derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) that actively clear inflammation to promote tissue homeostasis. Aspirin, in addition to exerting antithrombotic actions, also triggers the biosynthesis of these specialized pro-resolving mediators. Here, we used metabolomic profiling to investigate the biosynthesis of E-series resolvins with specific chiral chemistry in serum from human subjects and present evidence for new 18S series resolvins. Aspirin increased endogenous formation of 18S-hydroxyeicosapentaenoate (18S-HEPE) compared with 18R-HEPE, a known resolvin precursor. Human recombinant 5-lipoxygenase used both enantiomers as substrates, and recombinant LTA 4 hydrolase (LTA4H) converted chiral 5S(6)-epoxide-containing intermediates to resolvin E1 and 18S-resolvin E1 (RvE1 and 18S-RvE1, respectively). 18S-RvE1 bound to the leukocyte GPCRs ChemR23 and BLT1 with increased affinity and potency compared with the R-epimer, but was more rapidly inactivated than RvE1 by dehydrogenase. Like RvE1, 18S-RvE1 enhanced macrophage phagocytosis of zymosan, E. coli, and apoptotic neutrophils and reduced both neutrophil infiltration and proinflammatory cytokines in murine peritonitis. These results demonstrate two parallel stereospecific pathways in the biosynthesis of E-series resolvins, 18R-and 18S-, which are antiinflammatory, pro-resolving, and non-phlogistic and may contribute to the beneficial actions of aspirin and ω-3 polyunsaturated fatty acids.

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Section: Figurementioning

confidence: 99%

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Pillai²,

Recchiuti³

et al. 2011

J. Clin. Invest.

254

305

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“…6,25 The concept that COX-2 is the only COX isoform involved in inflammation has been challenged by a number of studies. 10,21,35 It is now believed that COX-1 is responsible for the initial prostanoid response to inflammatory stimuli, while COX-2 becomes the major contributor to prostanoid synthesis as inflammation progresses. 9,16,31 PGE 2 can be produced by PGE synthase from many different cell types including neurons, endothelial cells, and neutrophils.…”

Section: Introductionmentioning

confidence: 99%

Expression of COX-1 and COX-2 in a Clinical Model of Acute Inflammation

Khan

Iadarola

Yang

et al. 2007

The Journal of Pain

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Cyclooxygenase (COX) plays an important role in the induction of pain and inflammation as well as the analgesic actions of NSAIDs and coxibs. This study evaluates the expression of the two isoforms COX-1 and COX-2 in a clinical model in which the surgical removal of impacted third molars is used to evaluate the analgesic activity of anti-inflammatory drugs. A 3 mm punch biopsy was performed on the oral mucosa overlying one impacted third molar immediately before extraction of two impacted lower third molars. After the second tooth was extracted, a second biopsy was performed adjacent to the surgical site either immediately after surgery, 30, 60 or 120 minutes after surgery. RNA was extracted from the biopsies and RT-PCR was performed to assess mRNA levels of COX-1, COX-2 and glyceraldehyde-3-phosphate dehydrogenase (G3PDH). The RT-PCR products in the biopsies were normalized to G3PDH and compared to baseline. COX-2 mRNA was progressively increased at 30, 60, and 120 minutes after surgery (P<0.05); COX-1 mRNA was transiently decreased at 60 minutes during the post-surgical period (P<0.05). The results demonstrate peripheral elevation of COX-2 following tissue injury, which may contribute to increased prostaglandin E 2 at the site of injury, pain onset and the analgesic activity of both non-selective NSAIDs and selective COX-2 inhibitors.Perspective-This clinical study uses a physiologically relevant model to determine the time course of expression of COX -1 and -2 in acute inflammation of the human oral mucosa. This study furthers our understanding of the contribution of the COX isoforms to acute pain.

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“…Urinary TxB 2 was markedly elevated,~15 times, in 455 septic patients who were enrolled in the Ibuprofen in Sepsis Study Group (12). In healthy volunteers, LPS causes a dose-dependent increase in the excretion of TxB 2 concomitant with the stimulation of COX expression in monocytes and neutrophils (13). Moreover, it has been demonstrated in cultured leukocytes that COX-2 expression is inducible, mediated through Toll-like receptor 4 (TLR-4) activation by LPS and NF-B (14).…”

mentioning

confidence: 99%

Thromboxane Receptor Mediates Renal Vasoconstriction and Contributes to Acute Renal Failure in Endotoxemic Mice

Boffa

Just²,

Coffman

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Sepsis is a major cause of acute renal failure (ARF) and death. Thromboxane A2 (TxA 2 ) may mediate decreases of renal blood flow (RBF) and/or GFR associated with LPSinduced sepsis. This study tested whether TxA 2 receptor blockade, with the use of TxA 2 receptor knockout (TP-KO) mice or a selective TP receptor antagonist (SQ29,548), would alleviate LPS-induced renal vasoconstriction and ARF. Under basal conditions, anesthetized TP-KO mice displayed a lower mean arterial pressure than wild-type (WT) mice (102 versus 94 mmHg; P Ͻ 0.05). RBF, renal vascular resistance (RVR), GFR, and urine flow did not differ among groups under basal conditions, suggesting little tonic influence of TxA 2 on renal TP receptors in health. In endotoxemic WT mice, 14 h after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean arterial pressure was reduced to 85 mmHg (P Ͻ 0.001), as were RBF (5.0 versus 9.3 ml/min per g kidney wt; P Ͻ 0.001) and GFR (0.38 versus 1.03 ml/min per g kidney wt; P Ͻ 0.001). Heart rate and RVR (71 versus 47 mmHg/ml per min; P Ͻ 0.05) increased. The decreases in RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice (both P Ͻ 0.05). In both TP-KO and TP antagonist-treated mice, RVR remained stable in response to LPS versus WT mice that did not receive LPS. Delayed TP-antagonist treatment (12 h after LPS injection) ameliorated RBF and RVR but did not restore GFR. In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR. These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors.

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Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation

Cited by 211 publications

References 78 publications

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

Expression of COX-1 and COX-2 in a Clinical Model of Acute Inflammation

Thromboxane Receptor Mediates Renal Vasoconstriction and Contributes to Acute Renal Failure in Endotoxemic Mice

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