Pyrrolizidine alkaloids such as monocrotaline (MCT) are produced by plants which intoxicate humans and livestock in the U.S. and other countries. MCT produces lung injury accompanied by pulmonary hypertension and right ventricular hypertrophy (RVH) in experimental animals. Its pathophysiology shares much in common with certain types of chronic pulmonary hypertension in humans, and thus provides a good animal model for such human disease. A reactive pyrrole metabolite (MCTP) of MCT is thought to be the proximate toxicant, but its mechanism of toxicity is unknown. The most striking changes in pulmonary morphology in MCT intoxication includes alterations in vascular endothelium and accumulation in vessels of thrombi containing large numbers of platelets. The endothelial cell injury is associated with diminished capacity of the lungs to inactivate circulating 5-hydroxytryptamine (5HT). Thrombocytopenia reduces the degree of RVH following treatment with MCTP, suggesting a role for the platelet in the toxicology of this agent. The overall goal of the proposed research is to elucidate the role of the platelet in the cardiopulmonary toxicology of MCTP. Although the platelet could be involved in many ways, efforts for this granting period will focus upon the involvement of 5HT and of thromboxane A2 (TxA2). These are released by platelets and cause pulmonary vasoconstriction and platelet activation and thus may mediate the pulmonary hypertensive response to MCTP. Experiments will be performed to determine platelet kinetics and 5HT turnover in MCTP-intoxicated rats. The distribution of 5HT between platelets and plasma will also be examined. The isolated lung preparation will be used to determine if altered interactions between perfused platelets and lung occur after MCTP treatment which affect 5HT distribution, disposition or action or which alter the balance between TxA2 and prostacyclin (PGI2). Experiments with platelet-rich plasma will test whether uptake or release of 5HT by platelets is altered and whether the ability of platelets to generate and release TxA2 in changed in rats intoxicated with MCTP. The cardiopulmonary toxicity of MCTP will be compared in the fawn-hooded rat, a strain with a defect in 5HT storage and release. Finally, studies in vivo will determine effects on MCTP toxicity of drugs which are 5HT or thromboxane biosynthesis inhibitors or receptor antagonists. These studies will increase understanding of the role of the platelet in the responses of lung to chronic vascular injury from toxic agents. Such an understanding may lead to useful measures to prevent or to treat human pulmonary hypertension and right heart failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37ES002581-15
Application #
2153151
Study Section
Special Emphasis Panel (NSS)
Project Start
1981-04-01
Project End
1998-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
15
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Wagner, James G; Harkema, Jack R; Roth, Robert A (2002) Pulmonary leukostasis and the inhibition of airway neutrophil recruitment are early events in the endotoxemic rat. Shock 17:151-8
Wagner, J G; Roth, R A (2000) Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol Rev 52:349-74
Wagner, J G; Roth, R A (1999) Neutrophil migration during endotoxemia. J Leukoc Biol 66:10-24
Wagner, J G; Driscoll, K E; Roth, R A (1999) Inhibition of pulmonary neutrophil trafficking during endotoxemia is dependent on the stimulus for migration. Am J Respir Cell Mol Biol 20:769-76
Schultze, A E; Roth, R A (1998) Chronic pulmonary hypertension--the monocrotaline model and involvement of the hemostatic system. J Toxicol Environ Health B Crit Rev 1:271-346
Lappin, P B; Ross, K L; King, L E et al. (1998) The response of pulmonary vascular endothelial cells to monocrotaline pyrrole: cell proliferation and DNA synthesis in vitro and in vivo. Toxicol Appl Pharmacol 150:37-48
Lappin, P B; Roth, R A (1997) Hypertrophy and prolonged DNA synthesis in smooth muscle cells characterize pulmonary arterial wall thickening after monocrotaline pyrrole administration to rats. Toxicol Pathol 25:372-80
Schultze, A E; Emeis, J J; Roth, R A (1996) Cellular fibronectin and von Willebrand factor concentrations in plasma of rats treated with monocrotaline pyrrole. Biochem Pharmacol 51:187-91
Hoorn, C M; Wagner, J G; Petry, T W et al. (1995) Toxicity of mitomycin C toward cultured pulmonary artery endothelium. Toxicol Appl Pharmacol 130:87-94
Boor, P J; Gotlieb, A I; Joseph, E C et al. (1995) Chemical-induced vasculature injury. Summary of the symposium presented at the 32nd annual meeting of the Society of Toxicology, New Orleans, Louisiana, March 1993. Toxicol Appl Pharmacol 132:177-95

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