Summary
Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotalinetreated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dosedependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Astrup T, Albrechtsen OK (1957) Estimation of the plasminogen activator and the trypsin inhibitor in animal and human tissues. Scand J Clin Lab Invest 9:233–243
Cheeke PR, Pierson-Goeger ML (1983) Toxicity ofSenecio jacobaea and pyrrolizidine alkaloids in various laboratory animals and avian species. Toxicol Lett 18:343–349
Crapo JD, Tierney DF (1974) Superoxide dismutase and pulmonary oxygen toxicity. Am J Physiol 226:1401–1407
Cushman DW, Cheung HS (1971) Spectrophotometric assay and properties of the angiotensin-converting enzyme of rabbit lung. Biochem Pharmacol 20:1637–1648
Czer GT, Marsh J, Konopka R, Moser KM (1986) Low-dose PGI2 prevents monocrotaline-induced thromboxane production and lung injury. J Appl Physiol 60:464–471
Ganey PE, Fink GD, Roth RA (1985) The effect of dietary restriction and altered sodium intake on the cardiopulmonary toxicity of monocrotaline pyrrole. Toxicol Appl Pharmacol 78:55–62
Harris PN, Anderson RC, Chen KK (1942) The action of senecionine, integerrimine, jacobine, longilobine, and spartioidine, especially on the liver. J Pharmacol Exp Ther 75:69–77
Hayashi Y, Kato M, Otsuka H (1979) Inhibitory effects of diet reduction on monocrotaline intoxication in rats. Toxicol Lett 3:151–155
Hilliker KS, Roth RA (1984) Alteration of monocrotaline pyrrole-induced cardiopulmonary effects in rats by hydrallazine, dexamethasone or sulphinpyrazone. Br J Pharmacol 82:375–380
Hirai K (1980) Studies on the functional roles of taurine in the myocardium. J Kyoto Prefect Univ Med 89:37–50
Hooper PT (1974) The pathology ofSenecio jacobaea poisoning in mice. J Pathol 113:227–230
Johnson WD, Robertson KA, Pounds JG, Allen JR (1978) Dehydroretronecine-induced skin tumors in mice. J Natl Cancer Inst 61:85–89
Kay JM, Heath D (1969) Crotalaria spectabilis: The Pulmonary Hypertension Plant. Thomas, Springfield, IL
Miller WC, Rice DL, Kreusel RG, Bedrossian CWM (1978) Monocrotaline model of noncardiogenic pulmonary edema in dogs. J Appl Physiol 45:962–965
Miranda CL, Reed RL, Cheeke PR, Buhler DR (1981) Protective effects of butylated hydroxyanisole against the acute toxicity of monocrotaline in mice. Toxicol Appl Pharmacol 59:424–430
Miranda CL, Henderson MC, Schmitz JA, Buhler DR (1983) Protective role of dietary butylated hydroxyanisole against chemical-induced acute liver damage in mice. Toxicol Appl Pharmacol 69:73–80
Molteni A, Ward WF, Ts’ao C, Solliday NH (1984) Monocrotaline-induced pulmonary endothelial dysfunction in rats. Proc Soc Exp Biol Med 176:88–94
Molteni A, Ward WF, Ts’ao C, Solliday NH (1985) Monocrotaline-induced pulmonary fibrosis in rats: amelioration by Captopril and penicillamine. Proc Soc Exp Biol Med 180:112–120
Molteni A, Ward WF, Ts’ao C, Solliday NH (1986) Monocrotaline-induced cardiopulmonary damage in rats: amelioration by the angiotensin-converting enzyme inhibitor CL242817. Proc Soc Exp Biol Med 182:483–493
Molteni A, Ward WF, Ts’ao C, Solliday NH (1987) Monocrotaline-induced cardiopulmonary injury in rats: modification by thiol and nonthiol ACE inhibitors. Clin Exp Hypertens 9A:381–385
Zar JH (1974) Biostatistical Analysis. Prentice-Hall, Englewood Cliffs, NJ
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Molteni, A., Ward, W.F., Ts’ao, Ch. et al. Monocrotaline pneumotoxicity in mice. Virchows Archiv B Cell Pathol 57, 149–155 (1989). https://doi.org/10.1007/BF02899076
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02899076