Direct Inhibition of Catalase by Monocrotaline Pyrrole Induces Pulmonary Hypertension through Enhanced EGFR Signaling

2010 ◽  
Vol 49 ◽  
pp. S49
Author(s):  
Olga Rafikova ◽  
Ruslan Rafikov ◽  
Stephen M Black
Keyword(s):  
Pulmonary Hypertension ◽  
Egfr Signaling ◽  
Direct Inhibition ◽  
Monocrotaline Pyrrole

Effects of thrombocytopenia on monocrotaline pyrrole-induced pulmonary hypertension

1984 ◽  
Vol 246 (6) ◽  
pp. H747-H753 ◽  
Author(s):  
K. S. Hilliker ◽  
T. G. Bell ◽  
D. Lorimer ◽  
R. A. Roth
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Blood Platelet ◽  
Lavage Fluid ◽  
Right Ventricular Hypertrophy ◽  
Lactate Dehydrogenase Activity ◽  
Hypertrophic Response ◽  
Monocrotaline Pyrrole

Monocrotaline pyrrole (MCTP) causes lung injury, pulmonary hypertension, and right ventricular hypertrophy in rats. To determine if platelets are involved in the cardiopulmonary effects of MCTP, the response to MCTP was determined in thrombocytopenic rats. Blood platelet count was reduced to 10–20% of normal for 48 h by ip administration of an antirat platelet serum (PAS) prepared in the goat. Rats were treated iv with either MCTP 5 mg/kg or dimethylformamide vehicle and with either PAS or preimmune serum. Fourteen days after MCTP, right ventricular hypertrophy and several indexes of lung injury were measured. MCTP treatment produced right ventricular hypertrophy, increased lactate dehydrogenase activity and protein concentration in bronchopulmonary lavage fluid, increased perfusion pressure in isolated lungs, and decreased pulmonary clearance and metabolism of perfused 5-hydroxytryptamine. Thrombocytopenia did not influence the changes in these indexes of lung injury produced by MCTP in this protocol. When PAS was given 12 h before MCTP, it did not affect right ventricular hypertrophy, but when PAS treatment was begun 3 or 6 days after MCTP, right ventricular hypertrophy was decreased by 19 or 41%, respectively. These results suggest that platelets help to mediate the development of pulmonary hypertension and the hypertrophic response of the right heart following MCTP administration.

Effect of monocrotaline pyrrole on cultured cell cytoskeletons: An ultrastructural study

1991 ◽  
Vol 49 ◽  
pp. 122-123
Author(s):  
J.I. Wood ◽  
K.L. Klomparens ◽  
C.M. Hoorn ◽  
R.A. Roth ◽  
J. Reindel
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Cell Division ◽  
Alkylating Agent ◽  
Pyrrolizidine Alkaloid ◽  
Cell Structure ◽  
Plant Toxin ◽  
Monocrotaline Pyrrole ◽  
Intracellular Motility

The cytoskeleton (CS) is responsible for locomotion, intracellular motility and maintenance of cell structure. The system is composed of three major components: microfilaments, responsible for motility and cell structure, microtubules for organization and movement within the cell, and intermediate filaments, which may provide stability of intracellular contents.Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin. When administered to rats, MCT is metabolized to monocrotaline pyrrole (MCTP) which induces lung injury and pulmonary hypertension. When administered to cultured pulmonary artery endothelial cells, MCTP causes progressive detachment, release of LDH, inhibition of cell proliferation, and distorted and enlarged nuclei. MCTP is a bifunctional alkylating agent that can crosslink DNA. We speculate that MCTP may also affect the cytoskeleton, resulting in inhibition of cell division.

Ligand Independent Up-regulation of EGFR Signaling is Responsible for eNOS Dysfunction in Pulmonary Hypertension

2010 ◽  
Vol 49 ◽  
pp. S49
Author(s):  
Olga Rafikova ◽  
Neetu Sud ◽  
Sanjiv Kumar ◽  
Saurabh Aggarwal ◽  
Ruslan Rafikov ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Egfr Signaling

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.

scholarly journals Monocrotaline pyrrole induces pulmonary endothelial damage through binding to and release from erythrocytes in lung during venous blood reoxygenation

2019 ◽  
Vol 316 (5) ◽  
pp. L798-L809 ◽  
Author(s):  
Rui Xiao ◽  
Liping Zhu ◽  
Yuan Su ◽  
Jiwei Zhang ◽  
Yankai Lu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Partial Pressure ◽  
Venous Blood ◽  
Endothelial Damage ◽  
Toxic Metabolite ◽  
Partial Pressure Of Oxygen ◽  
Standard Dosage ◽  
Arterial Blood ◽  
Monocrotaline Pyrrole

Monocrotaline has been widely used to establish an animal model of pulmonary hypertension, most frequently in rats. An important feature of this model resides in the selectivity of monocrotaline injury toward the pulmonary vascular endothelium versus the systemic vasculature when administrated at standard dosage. The toxic metabolite of monocrotaline, monocrotaline pyrrole, is transported by erythrocytes. This study aimed to reveal whether partial pressure of oxygen of blood determined the binding and release of monocrotaline pyrrole from erythrocytes in rats with one subcutaneous injection of monocrotatline at the standard dosage of 60 mg/kg. Our experiments demonstrated that monocrotaline pyrrole bound to and released from erythrocytes at the physiological levels of partial pressure of oxygen in venous and arterial blood, respectively, and then aggregated on pulmonary artery endothelial cells. Monocrotaline pyrrole-induced damage of endothelial cells was also dependent on partial pressure of oxygen. In conclusion, our results demonstrate the importance of oxygen partial pressure on monocrotaline pyrrole binding to erythrocytes and on aggregation and injury of pulmonary endothelial cells. We suggest that these mechanisms contribute to pulmonary selectivity of this toxic injury model of pulmonary hypertension.

Thromboxane does not mediate pulmonary vascular response to monocrotaline pyrrole

1987 ◽  
Vol 252 (4) ◽  
pp. H743-H748
Author(s):  
P. E. Ganey ◽  
R. A. Roth
Keyword(s):  
Pulmonary Hypertension ◽  
Lactate Dehydrogenase ◽  
Right Ventricular ◽  
Dehydrogenase Activity ◽  
Protein Concentration ◽  
Ventricular Hypertrophy ◽  
Lavage Fluid ◽  
Lung Weight ◽  
Lactate Dehydrogenase Activity ◽  
Monocrotaline Pyrrole

The possible involvement of thromboxane (Tx) in the pulmonary hypertension caused by monocrotaline pyrrole (MCTP) administration to rats was investigated by pharmacological intervention of Tx synthesis and action. The cyclooxygenase inhibitor, ibuprofen, at doses that inhibited platelet function and suppressed plasma Tx levels, did not attenuate MCTP-induced right ventricular hypertrophy or increased lung weight. Dazmegrel, an inhibitor of Tx synthetase, did not affect the MCTP-induced increase in lung weight or the elevation of lactate dehydrogenase activity or protein concentration in bronchopulmonary lavage fluid, despite significant reduction of the plasma concentration of Tx. Dazmegrel also did not alter the vascular leak or right ventricular hypertrophy due to administration of MCTP to rats. Finally, the Tx receptor antagonist L-640,035 was tested using a dosing regimen that reduced the increase in right ventricular pressure caused by a stable endoperoxide analogue in MCTP-treated rats. Cotreatment with L-640,035 did not attenuate the increase in lung weight, lavage fluid lactate dehydrogenase activity or protein concentration, or the pulmonary hypertension caused by MCTP. These results indicate that interference with Tx synthesis or action does not attenuate the toxic effects of MCTP and suggest that Tx is not necessary for the cardiopulmonary response to MCTP.

Monocrotaline Pyrrole-Induced Pulmonary Hypertension in Fawn-Hooded Rats with Platelet Storage Pool Deficiency: 5-Hydroxytryptamine Uptake by Isolated, Perfused Lungs

1983 ◽  
Vol 50 (04) ◽  
pp. 844-847 ◽  
Author(s):  
Katherine S Hilliker ◽  
Thomas G Bell ◽  
Robert A Roth
Keyword(s):  
Pulmonary Hypertension ◽  
Sprague Dawley ◽  
Platelet Storage ◽  
Sd Rats ◽  
Function Defect ◽  
Perfused Lung ◽  
Isolated Lungs ◽  
Monocrotaline Pyrrole ◽  
Platelet Functions

SummaryPlatelets are believed to be involved in the development of monocrotaline pyrrole (MCTP)-induced pulmonary hypertension. To help identify the role of the platelet, the cardiopulmonary toxicity of MCTP was examined in fawn-hooded (FH) rats, a strain with a platelet function defect. Both Sprague-Dawley (SD) and FH rats developed right ventricular hypertrophy and increased lung weights and exhibited decreased biogenic amine removal by isolated, perfused lung preparations after MCTP treatment. The responses of the FH rats were not significantly different from those of the SD rats, suggesting that platelet uptake and release of 5-hydroxytryptamine (5HT) are not the platelet functions involved in MCTP-induced pulmonary hypertension. The FH rats had an interesting strain-related difference from SD rats; isolated lungs from FH rats removed and metabolized a greater proportion of perfused 5HT than the SD rats.

scholarly journals Single-Dose Monocrotaline Pyrrole Injection as a Model of Pulmonary Endothelial Injury In Mice

2018 ◽  
Author(s):  
William Raoul ◽  
Anne Hulin ◽  
Guitanouch Saber ◽  
Catherine Boisnier ◽  
Saadia Eddahibi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Dysfunction ◽  
Pulmonary Inflammation ◽  
Right Ventricular Dysfunction ◽  
Mouse Lung ◽  
Vascular Effects ◽  
Monocrotaline Pyrrole ◽  
Enos Protein Expression ◽  
Significant Injury ◽  
Enos Protein

AbstractMonocrotaline (MCT) is a plant substance that induces severe pulmonary hypertension in several animals except for mice. The aim of our study was to state whether monocrotaline pyrrole (MCTp), the main monocrotaline metabolite, could induce significant injury in mouse lung when given intravenously. MCTp caused moderate pulmonary inflammation, remodelling of small distal vessels (percentage of muscularized arteries: 33,5 vs 20,6%, p≤0,0006) and a right ventricular dysfunction (RVSP 27,8mmHg vs 16,4mmHg, p≤0,0001; Fulton index 0,35 vs 0,26, p≤0,0007). These vascular effects were associated with a decrease in eNOS protein expression in lung tissues and resolved after 45 days. In conclusion, we developed a model of endothelial dysfunction and transient pulmonary hypertension in mice.

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