Unilateral paraquat-induced lung fibrosis: evolution of changes in lung fibronectin and collagen after graded degrees of lung injury.
We describe a model of pulmonary fibrosis in which doses of paraquat ranging from 0.001 mg/kg to 1.0 mg/kg were instilled into the right lung of rats. Lung injury, as measured by right lung lavage albumin content and differential neutrophil count, ranged from undetectable to extremely severe, depending on the dose. Lung fibrosis, as assessed by collagen content and electron microscopy, showed similar dose-response effects. Mortality was minimal. Lavage fibronectin increased after high doses of paraquat, peaked at 2 d postinjury, decreased sharply after 3 d and was normal by 7 d. The temporal pattern was similar to that for albumin. Cultured alveolar macrophages obtained at 4 d postinjury did not have significant increases in fibronectin release. Tissue fibronectin content increased more slowly than lavage fibronectin, peaking at 4 d postinjury, and was still elevated at 7 and 14 d postinjury. Incorporation of [35S]methionine into tissue fibronectin by lung explants obtained at different times postinjury showed a similar time course. Lung collagen content increased steadily between 4 and 14 d postinjury. We conclude that, in our model, graded degrees of lung injury and fibrosis can be produced by varying the dose of unilaterally instilled paraquat and that the increases in lavage fibronectin were related mainly to capillary permeability whereas increases in tissue fibronectin represented parenchymal synthesis. The time course of changes in lung tissue fibronectin and collagen was consistent with the proposed roles of fibronectin in tissue repair and fibrosis. The ability of our model to produce graduated degrees of lung injury and fibrosis should be useful in further studies on the pathogenesis of postinjury lung fibrosis.
Dubaybo
B A
BA
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Durr
R A
RA
Thet
L A
LA
D000418:Albumins / Q000032:analysis; D000818:Animals; D003094:Collagen / Q000032:analysis*; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000032:analysis*; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D010269:Paraquat / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains
D000418:Albumins; D005353:Fibronectins; D003094:Collagen; D010269:Paraquat; D006909:Hydroxyproline