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DOI: 10.1055/s-2006-934026
Acute lung injury induced by the pyrrolizidine alkaloid monocrotaline in mice
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and lethal conditions. The mortality rate of ALI/ARDS depends on the underlying cause, varying from <20% for traumatically- to >60% for sepsis-induced ALI/ARDS. The aim of this study was to develop an animal model of ALI in mice employing monocrotaline (MCT). The MCT induces endothelial injury and pulmonary hypertension in rats. The proposed mechanism of action includes activation of MCT by the liver to the putative electrophile monocrotaline pyrrole (MCTP), which causes endothelial injury in the pulmonary vasculature with subsequent remodeling of the precapillary vessels. It has been suggested that mice are deficient in the metabolism of this alkaloid. We therefore chemically dehydrated MCT to MCTP and injected it intravenously into mice. MCTP-treated mice exhibited a dose-dependent pneumotoxicity. Mice injected with 9mg/kg body weight were investigated at 3 days, 1, 2, 3 and 4 weeks after MCTP administration. Bronchoalveolar lavage, histology, lung compliance and computed tomography revealed pulmonary inflammatory and exudative reactions in the acute phase (1–5 days) while moderate lung fibrosis was present in the late stages (2–4 weeks), indicating major differences between mice and rats to MCT pneumotoxicity. ALI induced by MCTP in mice may be a valuable animal model to study the pathogenesis of ALI and to develop new therapeutic strategies.
Supported by DFG, SFB547 „Kardiopulmonales Gefäßsystem“. Rio Dumitrascu is supported by a predoctoral fellowship from Altana Pharma.