Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury

Zamora, Cynthia; Baron, David; Heffner, John E.

doi:10.1152/jappl.1993.74.1.224

Cited by 64 publications

(46 citation statements)

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“…[1][2][3][4][5][6][7][8] It is interesting to note that calcium channel blockers are first-choice drugs in the treatment of pulmonary hypertension. 23,42 The present results demonstrate that PKC translocation, K V channel inactivation, membrane depolarization, and L-type Ca 2ϩ channel activation are key events mediating TXA 2 -induced pulmonary vasoconstriction, establishing the rationale for the use of calcium channel blockers in pulmonary hypertension associated with increased vasoconstrictors such as TXA 2 and isoprostanes activating TP receptors.…”

Section: Cogolludo Et Al K V Channels and Pkc In Pulmonary Arteriesmentioning

confidence: 99%

“…In fact, TXA 2 has been involved in several forms of human and experimental pulmonary hypertension, including primary 2 and secondary pulmonary hypertension induced by sepsis, endotoxemia, heparin/protamine, leukotriene D 4 , microembolism, and ischemia-reperfusion. [3][4][5][6][7][8] TXA 2 contracts vascular smooth muscle by binding to specific G q/11 protein-coupled receptors (TP receptors), which leads to an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and sensitization of the contractile proteins to Ca 2ϩ . 9 -12 Activation of TP receptors is also involved in the vasoconstrictor effects of several isoprostanes, a novel class of arachidonic acid metabolites generated by oxygen free radical-mediated peroxidation of membrane phospholipids, used as markers for many disease states, including pulmonary hypertension.…”

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confidence: 99%

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Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Cogolludo

Moreno

Boscá

et al. 2003

Circulation Research

136

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Abstract-Voltage-gated K ϩ channels (K V ) and thromboxane A 2 (TXA 2 ) play critical roles in controlling pulmonary arterial tone under physiological and pathological conditions. We hypothesized that TXA 2 might inhibit K V channels, thereby establishing a link between these two major pathogenic pathways in pulmonary hypertension. The TXA 2 analogue U46619 inhibited I K(V) (E max ϭ56.1Ϯ3.9%, EC 50 ϭ0.054Ϯ0.019 mol/L) and depolarized pulmonary artery smooth muscle cells via activation of TP receptors. In isolated pulmonary arteries, U46619 simultaneously increased intracellular Ca 2ϩ concentration and contractile force, and these effects were inhibited by nifedipine or KCl (60 mmol/L). U46619-induced contractions were not altered by the inhibitors of tyrosine kinase genistein or Rho kinase Y-27632 but were prevented by the nonselective protein kinase C (PKC) inhibitors staurosporine and calphostin C. Furthermore, these responses were sensitive to Gö-6983 but insensitive to bisindolylmaleimide I and Gö-6976. Based on the specificity of these drugs, we suggested a role for an atypical PKC in U46619-induced effects. Thus, treatment with a PKC pseudosubstrate inhibitor markedly prevented the vasoconstriction, the inhibition of I K(V) , and the depolarization induced by U46619. Western blots showed a transient translocation of PKC from the cytosolic to the particulate fraction on stimulation with U46619. These results indicate that TXA 2 inhibits I K(V) , leading to depolarization, activation of L-type Ca 2ϩ channels, and vasoconstriction of rat pulmonary arteries. We propose PKC as a link between TP receptor activation and K V channel inhibition.

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Section: Cogolludo Et Al K V Channels and Pkc In Pulmonary Arteriesmentioning

confidence: 99%

mentioning

confidence: 99%

Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Cogolludo

Moreno

Boscá

et al. 2003

Circulation Research

136

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“…TXA 2 is a potent stimulator of platelet aggregation and smooth muscle contraction and may play a role as a mediator of myocardial infarction, atherosclerosis, and bronchial asthma (22). Increased activity of TXA 2 has also been implicated in several forms of human and experimental pulmonary hypertension, including pulmonary hypertension induced by sepsis (36), heparin/protamine (19), and ischemia-reperfusion (39).…”

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confidence: 99%

Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins

Ding¹,

Murray²

2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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[Ca 2ϩ ]i and myofilament Ca 2ϩ sensitivity in the pulmonary venous smooth muscle (PVSM) contractile response to the thromboxane A2 mimetic U-46619 and to assess the roles of PKC, tyrosine kinases (TK), and Rho-kinase (ROK) in that response. We tested the hypothesis that U-46619-induced contraction in PVSM is mediated by both increases in [Ca 2ϩ ]i and myofilament Ca 2ϩ sensitivity and that the PKC, TK, and ROK signaling pathways are involved. Isometric tension was measured in isolated endothelium-denuded (EϪ) canine pulmonary venous (PV) rings. In addition, [Ca 2ϩ ]i and tension were simultaneously measured in fura-2-loaded EϪ PVSM strips. U-46619 (0.1 nM-1 M) caused dose-dependent (P Ͻ 0.001) contraction in PV rings. U-46619 contraction was attenuated by inhibitors of L-type voltage-operated Ca 2ϩ channels (nifedipine, P Ͻ 0.001), inositol 1,4,5-trisphosphate-mediated Ca 2ϩ release (2-aminoethoxydiphenylborate, P Ͻ 0.001), PKC (bisindolylmaleimide I, P Ͻ 0.001), TK (tyrphostin A-47, P ϭ 0.014), and ROK (Y-27632, P ϭ 0.008). In PV strips, U-46619 contraction was associated with increases in [Ca 2ϩ ]i and myofilament Ca 2ϩ sensitivity. Both Ca 2ϩ influx and release mediated the early transient increase in [Ca 2ϩ ]i, whereas the late sustained increase in [Ca 2ϩ ]i only involved Ca 2ϩ influx. Inhibition of both PKC and ROK (P ϭ 0.006 and P ϭ 0.002, respectively), but not TK, attenuated the U-46619-induced increase in myofilament Ca 2ϩ sensitivity. These results suggest that U-46619 contraction is mediated by Ca 2ϩ influx, Ca 2ϩ release, and increased myofilament Ca 2ϩ sensitivity. The PKC, TK, and ROK signaling pathways are involved in U-46619 contraction. pulmonary vein; Ca 2ϩ homeostasis; myofilament Ca 2ϩ sensitivity THROMBOXANE A 2 (TXA 2 ) is a major product of arachidonic acid metabolism via the cyclooxygenase pathway. TXA 2 is a potent stimulator of platelet aggregation and smooth muscle contraction and may play a role as a mediator of myocardial infarction, atherosclerosis, and bronchial asthma (22). Increased activity of TXA 2 has also been implicated in several forms of human and experimental pulmonary hypertension, including pulmonary hypertension induced by sepsis (36), heparin/protamine (19), and ischemia-reperfusion (39).The TXA 2 analog, U-46619, is known to cause constriction of pulmonary veins (13). Pulmonary venous constriction can increase pulmonary capillary pressure and transvascular fluid flux to cause pulmonary edema, which can adversely affect blood oxygenation and right ventricular function. Agonistinduced vascular smooth muscle contraction is mediated by an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and/or an increase in myofilament Ca 2ϩ sensitivity. We are aware of only one study that has investigated the effects of TXA 2 on [Ca 2ϩ ] i in pulmonary veins (13). In that study, changes in tension in response to the TXA 2 analog, U-46619, were measured in pulmonary venous rings, whereas changes in [Ca 2ϩ ] i were measured separately in dispersed pulmonary venous smo...

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“…The initial phase occurs <2 h after reperfusion and Kupffer cells seem to be mainly responsible. COX-2 expression is usually induced at inflammatory sites, mostly on monocytes and macrophages, and produces harmful effects including pain, trauma and IRI [46]. During hepatic IRI, activated Kupffer cells release a variety of proinflammatory cytokines, including TNF-α, which is a central mediator in the inflammatory response in hepatic IRI [6,47].…”

Section: Discussionmentioning

confidence: 99%

Role of Preferential Cyclooxygenase-2 Inhibition by Meloxicam in Ischemia/Reperfusion Injury of the Rat Liver

et al. 2014

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Background: Ischemia/reperfusion injury (IRI) is one of the major clinical problems in liver and transplant surgery. Livers subjected to warm ischemia in vivo often show a severe dysfunction and the release of numerous inflammatory cytokines and arachidonic acid metabolites. Cyclooxygenase (COX)-2 is the inducible isoform of an intracellular enzyme that converts arachidonic acid into prostaglandins. The aim of the study was to evaluate the effect of COX-2 inhibition and the role of Kupffer cells in IRI of the liver. Methods: Male Wistar rats [250- 280 g body weight (BW)] were anesthetized and subjected to 30-min warm ischemia of the liver (Pringle's maneuver) and 60-min reperfusion after median laparotomy. The I/R group received no additional treatment. In the COX-2 inhibitor (COX-2I) group, the animals received 1 mg/kg BW meloxicam prior to operation. Gadolinium chloride (GdCl₃) (10 mg/kg BW) was given 24 h prior to operation in the GdCl₃ and GdCl₃ + COX-2I groups for the selective depletion of Kupffer cells. The GdCl₃ + COX-2I group received both GdCl₃ and meloxicam treatment prior to operation. Blood and liver samples were obtained at the end of the experiments for further investigations. Results: After 30 min of warm ischemia in vivo, severe hepatocellular damage was observed in the I/R group. These impairments could be significantly prevented by the selective COX-2 inhibition and the depletion of Kupffer cells. Alanine aminotransferase was significantly reduced upon meloxicam and GdCl₃ treatment compared to the I/R group: I/R, 3,240 ± 1,262 U/l versus COX-2I, 973 ± 649 U/l, p < 0.001; I/R versus GdCl₃, 1,611 ± 600 U/l, p < 0.05, and I/R versus GdCl₃ + COX-2I, 1,511 ± 575 U/l, p < 0.01. Plasma levels of tumor necrosis factor alpha (TNF-α) were significantly reduced in the COX-2I treatment group compared to I/R (3.5 ± 1.5 vs. 16.3 ± 11.7 pg/ml, respectively; p < 0.05). Similarly, the amount of TxB₂, a marker for COX-2 metabolism, was significantly reduced in the meloxicam treatment groups compared to the I/R group: I/R, 22,500 ± 5,210 pg/ml versus COX-2I, 1,822 ± 938 pg/ml, p < 0.001, and I/R versus GdCl₃ + COX-2I, 1,530 ± 907 pg/ml, p < 0.001. All values are given as mean ± SD (n = 6). Conclusion: These results suggest that the inhibition of COX-2 suppressed the initiation of an inflammatory cascade by attenuating the release of TNF-α, which is an initiator of the inflammatory reaction in hepatic IRI. Therefore, we conclude that preferential inhibition of COX-2 is a possible therapeutic approach against warm IRI of the liver.

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Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury

Cited by 64 publications

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Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins

Role of Preferential Cyclooxygenase-2 Inhibition by Meloxicam in Ischemia/Reperfusion Injury of the Rat Liver

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Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury

Cited by 64 publications

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Thromboxane A 2 -Induced Inhibition of Voltage-Gated K + Channels and Pulmonary Vasoconstriction

Thromboxane A 2 -Induced Inhibition of Voltage-Gated K + Channels and Pulmonary Vasoconstriction

Cellular mechanisms of thromboxane A2-mediated contraction in pulmonary veins

Role of Preferential Cyclooxygenase-2 Inhibition by Meloxicam in Ischemia/Reperfusion Injury of the Rat Liver

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Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Thromboxane A ₂ -Induced Inhibition of Voltage-Gated K ⁺ Channels and Pulmonary Vasoconstriction

Cellular mechanisms of thromboxane A₂-mediated contraction in pulmonary veins