Cyclooxygenase pathway mediates lung injury induced by phorbol and platelets

1991 ◽  
Vol 70 (6) ◽  
pp. 2417-2421 ◽  
Author(s):  
D. Wang ◽  
C. L. Chou ◽  
K. Hsu ◽  
H. I. Chen
Keyword(s):  
Lung Injury ◽  
Pulmonary Arterial Pressure ◽  
Nordihydroguaiaretic Acid ◽  
Thromboxane B2 ◽  
Myristate Acetate ◽  
Lung Weight ◽  
Edema Formation ◽  
Pulmonary Arterial

The role of platelets in lung injury has not been well defined. In the present study of isolated perfused rat lungs, phorbol myristate acetate (PMA; 0.15 microgram/ml) or platelets (6.7 X 10(4)/ml) alone did not discernibly change the pulmonary arterial pressure (PAP) or lung weight (LW). However, the combination of platelets and PMA drastically increased the PAP and LW (delta PAP 26.2 +/- 1.0 mmHg, delta LW 2.7 +/- 0.4 g). delta PAP was positively correlated with the increase in thromboxane B2 produced by infusion of platelets and PMA (thromboxane B2 = 35.6 + 0.97 delta PAP, r = 0.67, P less than 0.01). The hypertension and edema formation induced by PMA and platelets were strongly attenuated by indomethacin, an inhibitor of platelet cyclooxygenase (delta PAP 5.6 +/- 2.0 mmHg, P less than 0.001; delta LW 0.0 +/- 0.1 g, P less than 0.001), and by imidazole, an inhibitor of thromboxane A2 synthase (PAP 8.0 +/- 2.5 mmHg, P less than 0.001; LW 0.0 +/- 0.3 g, P less than 0.01). Inactivation of platelet lipoxygenase with nordihydroguaiaretic acid mildly depressed pulmonary pressure but did not affect delta LW (delta PAP 18.9 +/- 1.6 mmHg, P less than 0.05; delta LW 3.1 +/- 0.3 g, P greater than 0.05). In vitro experiments showed that the capacity of platelets to release oxygen radicals was only 2.6% of that found for granulocytes. These results suggest that platelets may be activated by PMA to increase PAP and vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperbaric oxygen toxicity: role of thromboxane

1992 ◽  
Vol 72 (2) ◽  
pp. 416-422 ◽  
Author(s):  
J. M. Jacobson ◽  
J. R. Michael ◽  
R. A. Meyers ◽  
M. B. Bradley ◽  
A. M. Sciuto ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Lavage Fluid ◽  
Thromboxane B2 ◽  
Lung Weight ◽  
Pulmonary Arterial

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248–01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)

PMA-induced pulmonary edema: mechanisms of the vasoactive response

1988 ◽  
Vol 65 (5) ◽  
pp. 2302-2312 ◽  
Author(s):  
A. Johnson
Keyword(s):  
Superoxide Dismutase ◽  
Pulmonary Arterial Pressure ◽  
Ringer Solution ◽  
Myristate Acetate ◽  
Lung Weight ◽  
Kinase C ◽  
Pulmonary Capillary ◽  
Capillary Filtration Coefficient ◽  
Pulmonary Capillary Pressure ◽  
Pulmonary Arterial

We investigated the effect of phorbol myristate acetate (PMA) in isolated guinea pig lungs perfused with phosphate-buffered Ringer solution. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight were recorded at 0, 10, 25, 40, and 70 min. The capillary filtration coefficient (Kf), an index of vascular permeability, was measured at 10 and 70 min. The perfusion of PMA (0.5 x 10(-7) M) increased Ppa, Ppc, and lung weight at 70 min. The ratio of arterial-to-venous vascular resistance (Ra/Rv) decreased and the Kf did not change with PMA. The perfusion of the lung with 4 alpha-phorbol didecanoate (inactive toward the protein kinase C analogue of PMA) did not affect the lung. The inhibition of TxA2 synthase with dazoxiben inhibited the response to PMA. The inhibition of the 5-lipoxygenase with U-60257 and the SRS-A receptor antagonist FPL 55712 also prevented the response to PMA. The addition of superoxide dismutase (SOD), catalase, or SOD plus catalase (the enzymes that remove O.2 H2O2, and OH., respectively) did not prevent the PMA effect or the release of TxA2; however, dimethylthiourea (DMTU), a scavenger of OH., did prevent the response to PMA. The data indicate that PMA causes a neutrophil-independent increase in lung weight due to increases in Ppc mediated by TxA2 and SRS-A. The protective effect of DMTU may be due to the inhibition of TxA2 generation.

scholarly journals Lipoxygenase metabolites of arachidonic acid modulate hematopoiesis

Blood ◽  
1986 ◽  
Vol 67 (6) ◽  
pp. 1675-1679 ◽  
Author(s):  
DS Snyder ◽  
JF Desforges
Keyword(s):  
Arachidonic Acid ◽  
Mononuclear Cells ◽  
Nordihydroguaiaretic Acid ◽  
Cell Types ◽  
Dependent Manner ◽  
Myristate Acetate ◽  
Human Erythropoietin ◽  
Dose Dependent

Abstract Lipoxygenase (LPO) metabolites of arachidonic acid participate in the activation and/or proliferation of a variety of cell types. In this study, we examined the role of LPO metabolites in controlling myelopoiesis and erythropoiesis in vitro. Monocyte depleted cells (MDC) prepared from human whole blood or whole mononuclear cells from human bone marrow were cultured in methylcellulose in the presence of various growth factors. Conditioned media containing human colony stimulating factors (CSF) or the tumor-promoting phorbol ester, phorbol myristate acetate (PMA), were added to induce myelopoiesis. Semipurified human erythropoietin (EPO) was added along with an endogenous source of burst- promoting activity (BPA) to induce erythropoiesis. The LPO inhibitor BW755C blocked all types of colony formation in a dose-dependent manner, with ID50 of 20 and 5 micrograms/mL for myeloid and erythroid colonies, respectively. MDC depleted of T cells were similarly inhibited by BW755C. Similar results were seen with two other LPO inhibitors, 1-phenyl-3-pyrazolidone and butylated hydroxyanisole. A fourth LPO inhibitor, nordihydroguaiaretic acid, inhibited at higher concentrations. Indomethacin, at concentrations that inhibit cyclooxygenase, had no significant effect, either alone or in combination with the LPO inhibitors. These results suggest that certain LPO products may be important mediators of both CSF- and PMA-induced myelopoiesis, and of BPA/EPO-induced erythropoiesis.

Air embolism-induced lung injury in isolated rat lungs

1992 ◽  
Vol 72 (4) ◽  
pp. 1235-1242 ◽  
Author(s):  
D. Wang ◽  
M. H. Li ◽  
K. Hsu ◽  
C. Y. Shen ◽  
H. I. Chen ◽  
...  
Keyword(s):  
Weight Gain ◽  
Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Air Embolism ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Lung Model ◽  
Lung Weight ◽  
Pulmonary Arterial

Pulmonary air embolism causes physical obstruction of microvasculature and leads to permeability changes, release of mediators, and injury to lung tissue. In this study we employed an isolated perfused rat lung model to investigate the primary and secondary effects produced by infusion of air into the pulmonary artery. Infusion of various doses of air (0.10–0.25 ml) over a 1-min period produced a dose-dependent increase in pulmonary arterial pressure and lung weight gain. In contrast, when a constant air dose was administered over various periods of time (0.25 ml over 0.5–8.0 min), the pulmonary arterial pressure rose to the same extent regardless of the infusion rate, whereas the lung weight gain increased proportionately with the rate of infusion. Total vascular resistance rose from 1.41 +/- 0.04 to 5.04 +/- 0.09 mmHg.ml-1.min in rats given 0.25 ml air over 1 min (n = 14, P less than 0.001), with greater than or equal to 90% of this increase occurring in the arterial segments. Both thromboxane B2 and endothelin concentrations also increased in the perfusate, suggesting their involvement in this increased resistance. Furthermore the pulmonary filtration coefficient increased from 0.21 +/- 0.05 to 1.28 +/- 0.26 g.min-1.cmH2O–1.100 g (n = 8, P less than 0.001), and the protein concentration in lung lavage fluid also rose, indicating lung injury. Leukocyte counts in the perfusate were unaffected by embolization, but chemiluminescent activity was increased, indicating a possible role for activated leukocytes in lung injury induced by air emboli.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic agents diminish thiourea-induced pulmonary vascular protein leak in rats

1987 ◽  
Vol 63 (5) ◽  
pp. 1877-1883 ◽  
Author(s):  
T. J. Stelzner ◽  
C. H. Welsh ◽  
E. Berger ◽  
R. G. McCullough ◽  
K. Morris ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Arterial Pressure ◽  
Dry Weight ◽  
H2o2 Production ◽  
Antiarrhythmic Agents ◽  
Mean Pulmonary Arterial Pressure ◽  
Wet Weight ◽  
Pulmonary Arterial ◽  
Lidocaine Pretreatment

Drugs possessing membrane stabilizing activity might act to diminish the augmented microvascular permeability resulting from acute lung injury. To test this rats were pretreated with quinidine, procainamide, or lidocaine and then given the lung injury-inducing agent thiourea. Vascular permeability, assessed as the extravascular accumulation of radiolabeled protein, was increased more than threefold by thiourea. This increase was diminished by 29, 34, and 43% after pretreatment with procainamide, quinidine, and lidocaine, respectively. Lidocaine also returned the thiourea-induced increase in lung wet weight-to-dry weight ratios to control levels. This protection was not likely due to hemodynamic effects of these agents, since no differences were noted in cardiac output between pretreated rats and those receiving thiourea alone and a small increase in mean pulmonary arterial pressure in the lidocaine-pretreatment group was the only difference noted. O2 metabolites have been implicated in the pathogenesis of thiourea-induced lung injury. None of these agents scavenged O2- or H2O2 directly, but quinidine and procainamide diminished in vitro neutrophil O2- and H2O2 production, and lidocaine inhibited neutrophil H2O2 production. However, neutropenia (PMN less than 100/ml) induced with either vinblastine or cyclophosphamide (Cytoxan) failed to prevent thiourea-induced increases in pulmonary vascular protein leak. In conclusion, procainamide, quinidine, and lidocaine diminished lung injury in rats after thiourea. Although these agents diminish PMN O2 metabolite production in vitro their salutary role in thiourea-induced lung injury appears to be through an unknown mechanism that is independent of their effects on neutrophil O2 metabolite-dependent toxicity.

scholarly journals Beyond Thrombosis: the Role of Platelets in Pulmonary Hypertension

2020 ◽  
Vol 2 (4) ◽  
pp. 243-271
Author(s):  
Salina Nicoleau ◽  
Beata Wojciak-Stothard
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Pressure ◽  
Right Heart Failure ◽  
Inflammatory Cells ◽  
The Past ◽  
Current State ◽  
Wide Range ◽  
Pulmonary Arterial

Pulmonary Hypertension (PH) is a multifactorial and lethal disease, characterised by elevated pulmonary arterial pressure and progressive right heart failure. PH pathobiology rests on four pillars: vascular remodelling, vasoconstriction, inflammation and thrombosis. While vascular and inflammatory cells have been the focus of PH research over the past decades, platelets have received relatively less attention, despite their associations with key pathophysiological processes of the disease. Platelets contain a wide range of vasoactive, inflammatory and pro-thrombotic mediators, likely to promote PH development and progression. There is currently no cure for PH, and platelet-associated pathways may help identify new therapeutic strategies. This review summarises available evidence on the role of platelets in different forms of PH, and comments on the current state of platelet-targeting therapies. It also describes the latest advances in the in vitro technologies that enable exploration of platelet function under dynamic and physiologically relevant conditions. Doi: 10.28991/SciMedJ-2020-0204-7 Full Text: PDF

scholarly journals Lipoxygenase metabolites of arachidonic acid modulate hematopoiesis

Blood ◽  
1986 ◽  
Vol 67 (6) ◽  
pp. 1675-1679
Author(s):  
DS Snyder ◽  
JF Desforges
Keyword(s):  
Arachidonic Acid ◽  
Mononuclear Cells ◽  
Nordihydroguaiaretic Acid ◽  
Cell Types ◽  
Dependent Manner ◽  
Myristate Acetate ◽  
Human Erythropoietin ◽  
Dose Dependent

Lipoxygenase (LPO) metabolites of arachidonic acid participate in the activation and/or proliferation of a variety of cell types. In this study, we examined the role of LPO metabolites in controlling myelopoiesis and erythropoiesis in vitro. Monocyte depleted cells (MDC) prepared from human whole blood or whole mononuclear cells from human bone marrow were cultured in methylcellulose in the presence of various growth factors. Conditioned media containing human colony stimulating factors (CSF) or the tumor-promoting phorbol ester, phorbol myristate acetate (PMA), were added to induce myelopoiesis. Semipurified human erythropoietin (EPO) was added along with an endogenous source of burst- promoting activity (BPA) to induce erythropoiesis. The LPO inhibitor BW755C blocked all types of colony formation in a dose-dependent manner, with ID50 of 20 and 5 micrograms/mL for myeloid and erythroid colonies, respectively. MDC depleted of T cells were similarly inhibited by BW755C. Similar results were seen with two other LPO inhibitors, 1-phenyl-3-pyrazolidone and butylated hydroxyanisole. A fourth LPO inhibitor, nordihydroguaiaretic acid, inhibited at higher concentrations. Indomethacin, at concentrations that inhibit cyclooxygenase, had no significant effect, either alone or in combination with the LPO inhibitors. These results suggest that certain LPO products may be important mediators of both CSF- and PMA-induced myelopoiesis, and of BPA/EPO-induced erythropoiesis.

Effect of leukopenia on pulmonary hypertension after heparin-protamine in pigs

1992 ◽  
Vol 73 (1) ◽  
pp. 44-49 ◽  
Author(s):  
H. Habazettl ◽  
P. F. Conzen ◽  
B. Vollmar ◽  
E. Yekebas ◽  
K. Peter
Keyword(s):  
Pulmonary Hypertension ◽  
Thromboxane A2 ◽  
Thromboxane B2 ◽  
Control Group ◽  
Mean Pulmonary Arterial Pressure ◽  
Leukocyte Counts ◽  
Pulmonary Arterial ◽  
Heparin Neutralization

Heparin neutralization by protamine after cardiac surgery and cardiopulmonary bypass may be associated with complement activation, transient leukopenia, thromboxane A2 release, and severe pulmonary hypertension. The role of leukocytes in the heparin-protamine reaction was studied in leukopenic pigs (n = 9) and a control group (n = 8). Leukopenia was induced by pretreatment with cyclophosphamide (30 mg.kg-1.day-1) for 6–7 days. During general anesthesia and after catheterization, baseline recordings of hemodynamics were performed and blood samples were withdrawn. Heparin (250 IU/kg) was injected and measurements were repeated after 10 min. Protamine sulfate (100 mg) was then infused over 2 min and measurements were performed after 2, 5, and 15 min. Prostanoid concentrations were measured by radioimmunoassays. In additional in vitro experiments, the release of thromboxane B2 from washed platelets and leukocytes after heparin-protamine stimulation was measured. Pretreatment with cyclophosphamide reduced leukocyte counts by 95.5% and the number of neutrophils by greater than 99.9%. Protamine infusion increased mean pulmonary arterial pressure by 74 and 46% and pulmonary vascular resistance by 185 and 384% in control and leukopenic animals, respectively. Thromboxane B2 concentrations increased in both groups. Stimulation by heparin, protamine, or heparin and protamine in sequence did not induce any thromboxane A2 release from washed blood cells. It is concluded that leukocytes do not contribute to pulmonary hypertension after heparin-protamine.

Pulmonary hypertension due to monocrotaline pyrrole is reduced by moderate thrombocytopenia

1988 ◽  
Vol 255 (5) ◽  
pp. H1165-H1172 ◽  
Author(s):  
P. E. Ganey ◽  
K. H. Sprugel ◽  
S. M. White ◽  
J. G. Wagner ◽  
R. A. Roth
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Lavage Fluid ◽  
Lung Weight ◽  
Lactate Dehydrogenase Activity ◽  
Pulmonary Arterial ◽  
Series Of Experiments ◽  
Monocrotaline Pyrrole

To elucidate further the role of the platelet in the development of monocrotaline pyrrole (MCTP)-induced lung injury and pulmonary hypertension, MCTP-treated rats were made thrombocytopenic by cotreatment with an anti-rat platelet serum (PAS). Lung injury was assessed from increases in lung weight, lavage fluid protein concentration, and lactate dehydrogenase activity and from accumulation in lung tissue of 125I-labeled albumin. These indexes of injury were not different in MCTP-treated rats with normal or reduced platelet numbers at day 4,8, or 14. In MCTP-treated rats not receiving the PAS, pulmonary arterial pressure was elevated by day 8. However, pulmonary arterial pressure was the same as controls at both day 8 and day 14 in MCTP-treated rats made moderately thrombocytopenic by cotreatment with PAS. More marked reduction of platelet number abolished the protective effect of thrombocytopenia against pulmonary hypertension. In a separate series of experiments, treatment with antibodies to platelet-derived growth factor (PDGF), a potential mediator in the response to MCTP-induced injury, did not protect rats from the cardiopulmonary effects of MCTP. These data indicate that moderate reduction of the number of circulating platelets prevents MCTP-induced pulmonary hypertension but not MCTP-induced lung injury, suggesting that the platelet is involved in the pulmonary hypertensive response to MCTP-induced lung injury by unknown mechanisms.

Intratracheal administration of DBcAMP attenuates edema formation in phosgene-induced acute lung injury

1996 ◽  
Vol 80 (1) ◽  
pp. 149-157 ◽  
Author(s):  
A. M. Sciuto ◽  
P. T. Strickland ◽  
T. P. Kennedy ◽  
Y. L. Guo ◽  
G. H. Gurtner
Keyword(s):  
Lung Injury ◽  
Lung Model ◽  
Rabbit Lung ◽  
Lung Weight ◽  
Edema Formation ◽  
Intratracheal Administration ◽  
Reduced And Oxidized Glutathione ◽  
Life Threatening ◽  
Glutathione Oxidation ◽  
Pulmonary Arterial

Phosgene, a toxic gas widely used as an industrial chemical intermediate, is known to cause life-threatening latent noncardiogenic pulmonary edema. Mechanisms related to its toxicity appear to involve lipoxygenase mediators of arachidonic acid (AA) and can be inhibited by pretreatment with drugs that increase adenosine 3′,5′-cyclic monophosphate (cAMP). In the present study, we used the isolated buffer-perfused rabbit lung model to investigate the mechanisms by which cAMP protects against phosgene-induced lung injury. Posttreatment with dibutyryl cAMP (DBcAMP) was given 60-85 min after exposure by an intravascular or intratracheal route. Lung weight gain (LWG) was measured continuously. AA metabolites leukotriene (LT) C4, LTD4, and LTE4 and 6-ketoprostaglandin F1 alpha were measured in the perfusate at 70, 90, 110, 130, and 150 min after exposure. Tissue malondialdehyde and reduced and oxidized glutathione were analyzed 150 min postexposure. Compared with measurements in the lungs of rabbits exposed to phosgene alone, posttreatment with DBcAMP significantly reduced LWG, pulmonary arterial pressure, and inhibited the release of LTC4, LTD4, and LTE4. Intratracheal administration of DBcAMP was more effective than intravascular administration in reducing LWG. Posttreatment also decreased MDA and protected against glutathione oxidation observed with phosgene exposure. We conclude that phosgene causes marked glutathione oxidation, lipid peroxidation, release of AA mediators, and increases LWG. Posttreatment with DBcAMP attenuates these effects, not only by previously described inhibition of pulmonary endothelial or epithelial cell contraction but also by inhibition of AA-mediator production and a novel antioxidant effect.

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