title: Monokine-induced lung injury in rats: similarities to monocrotaline-induced pneumotoxicity.
abstract: Previous studies have shown that abnormal alveolar macrophages and biological activity resembling the macrophage-derived mediator interleukin-1 (IL-1) can be detected in bronchoalveolar lavage fluid from rats with monocrotaline-induced lung injury and pulmonary hypertension. To determine if monokines might play a pathogenic role in this model, the present study evaluated the effects of a murine monokine preparation enriched in IL-1 bioactivity on selected events characterizing the early pneumotoxic response to monocrotaline, including pulmonary edema and protein extravasation, pulmonary vascular hyperreactivity, and enhanced lung tissue activity of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). Intravenous injection of the monokine preparation containing 200 units/kg IL-1 (quantified by lymphocyte activating factor assay) into intact rats produced pulmonary edema within 3 hr manifested by increases in the lung wet-to-dry weight ratio and in the extent of pulmonary albumin extravasation. The edema had resolved within 24 hr of monokine administration as indicated by a return to control levels of the wet-to-dry weight ratio and albumin extravasation index. The monokine preparation also increased the transfer of albumin across monolayers of cultured porcine pulmonary vascular endothelial cells. While salt solution-perfused rat lungs isolated from animals treated 3 hr previously with the monokine preparation were hyporesponsive to angiotensin II, preparations derived from animals treated 24 hr previously were markedly hyperresponsive to the vasoconstrictor actions of the peptide. Pressor responses to potassium chloride and prostaglandin F2a were unaffected by exposure to the monokine preparation. Lung ODC activity in monokine-exposed animals did not differ from control at 3, 6, or 24 hr after treatment. In contrast, a 24-hr exposure of cultured pulmonary vascular endothelial cells to the monokine preparation increased ODC activity approximately 100-fold. These observations indicate that a monokine preparation containing IL-1 bioactivity causes transient pulmonary edema and pulmonary vascular hyperreactivity and increases ODC activity in pulmonary vascular endothelial cells. Because the monokine preparation mimics certain aspects of monocrotaline-induced pneumotoxicity in the rat, it is reasonable to postulate that monokines could play a pathogenic role in this and similar animal models of lung injury and pulmonary hypertension.
authors.affiliation: University of Kentucky College of Pharmacy, Division of Pharmacology and Toxicology, College of Medicine, Lexington.
authors.forename: M N
authors.initials: MN
authors.lastname: Gillespie
authors.forename: J W
authors.initials: JW
authors.lastname: Olson
authors.forename: B
authors.initials: B
authors.lastname: Hennig
authors.forename: D A
authors.initials: DA
authors.lastname: Cohen
authors.forename: C J
authors.initials: CJ
authors.lastname: McClain
authors.forename: S E
authors.initials: SE
authors.lastname: Goldblum
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000633:toxicity*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D006976:Hypertension, Pulmonary / Q000139:chemically induced; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D015846:Monokines; D009929:Organ Size / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010477:Perfusion; D011654:Pulmonary Edema / Q000139:chemically induced; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D001685:Biological Factors; D015846:Monokines; D011763:Pyrrolizidine Alkaloids; D012709:Serum Albumin; D016686:Monocrotaline; D009955:Ornithine Decarboxylase