The lung has a unique toxicology in that it receives xenobiotics both from the circulation and by inhalation. Substances absorbed from the gastrointestinal tract pass through the liver, and they and their metabolites are then delivered to the lung, the next organ in line, in a relatively concentrated form. The pyrrolizidine alkaloids comprise a major group of hepato and pneumotoxins exhibiting many aspects of scientific and clinical interest. These substances are hepatic mitogens and carcinogens, produce megalocytosis and cirrhosis of the liver, and can also damage the cardiopulmonary system, producing pulmonary arterial hypertension, right ventricular hypertrophy, and cor pulmonale. This pattern of toxicity is due to a complex interaction of metabolism, transport, reaction and degradation in the liver, blood, lungs and right heart. Pyrrolizidine poisoning is a major public health problem. Widespread outbreaks occur in the underdeveloped nations as a result of food contamination and the folk medicinal use of pyrrolizidine-containing plants. In the industrialized nations, poisonings occur as a result of the use of pyrrolizidine-containing food supplements. Intoxication of livestock is a significant economic problem in the United States, and may also result in an unknown degree of contamination of food supplies. This study aims to uncover the metabolites which are severally responsible for liver, lung and heart toxicity. By what mechanism does acute exposure to pyrrolizidines result in a chronically developing disease? The solution to this intriguing problem lies in a study both of organ to organ and of cell to cell interactions. At the organ level, it appears that certain metabolites produced in the liver damage the liver, while other metabolites are released to damage the lungs. It is possible that the right heart damage developes in reaction to the lung damage. At the cellular level, substances released from hepatocytes damage the endothelium in the liver, leading to portal hypertension, whereas in the lung it is possible that damage to endothelium affects the release of other mediators that modulate the response of vascular smooth muscle. The complex mechanisms of pyrrolizidine alkaloid poisoning are not only of intrinsic interest, but will yield insight into the molecular mechanisms whereby pulmonary arterial hypertension, right ventricular hypertrophy, and cor pulmonary develop. In addition, the mechanisms of pyrrolizidine poisoning can serve as a general paradigm for liver-lung interactions.
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