Environmental Health Perspectives 105, Supplement 5, September 1997

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Early Mesothelial Cell Proliferation after Asbestos Exposure: In Vivo and in Vitro Studies

Ian Y.R. Adamson

Department of Pathology, University of Manitoba, Winnipeg, Canada

Abstract
There is some evidence that proliferation of pleural mesothelial cells (MC) occurs soon after deposition of asbestos fibers. To study this effect, we instilled a single dose of 0.1 mg crocidolite into the lungs of mice for 1 and 6 weeks and counted labeled nuclei after 3 H-thymidine ( 3 HT) injection. Short fibers (<1 µm) induced little change in the lung; they were mostly phagocytized and had a minimal effect on MC labeling. Long fibers up to 20 µm damaged the bronchiolar epithelium and were incorporated into connective tissue. Increased 3 HT uptake was seen in fibroblasts and epithelial cells and also in MC, which peaked at 2% labeled at 1 week compared to near 0% labeling in controls. No fibers were found in or near labeled MC, which suggested that a cytokine generated in the lung during the early response phase might induce MC proliferation. To look for a cytokine effect in vitro , we instilled asbestos into rat lungs and, after 1 and 6 weeks, bronchoalveolar and pleural lavage fluids as well as macrophages were collected. Alveolar macrophages contained fibers, but pleural macrophages (PM) did not. After short-term culture, macrophage supernatants and the lavage fluids were tested on rat lung MC in culture. At 1 week, PM secreted growth factor(s) for MC, and the mitogenic effect was more pronounced with lavage fluids. No effects on MC were found using material prepared 6 weeks after asbestos. The early MC growth increase was not blocked by antibodies to cytokines, such as platelet-derived growth factor, fibroblast growth factors, or tumor necrosis factor, but was inhibited by anti-keratinocyte growth factor (anti-KGF). The results show that an early growth phase of MC after asbestos exposure appears unrelated to particle translocation to the pleura but is associated with cytokine release, most likely KGF, by lung cells. -- Environ Health Perspect 105(Suppl 5):1205-1208 (1997)

Key words : lung, mesothelial cells, asbestos, pleural disease

This paper is based on a presentation at The Sixth International Meeting on the Toxicology of Natural and Man-Made Fibrous and Non-Fibrous Particles held 15-18 September 1996 in Lake Placid, New York. Manuscript received at EHP 27 March 1997; accepted 6 May 1997.

This research project was supported by a grant from the Medical Research Council of Canada.

Address correspondence to Dr. I.Y.R. Adamson, Department of Pathology, University of Manitoba, D212-770 Bannatyne Avenue, Winnipeg, Canada R3E 0W3. Telephone: (204) 789-3539. Fax: (204) 774-9018. E-mail: iadamsn@cc.umanitoba.ca

Abbreviations used: AM, alveolar macrophage(s); BALF, bronchoalveolar lavage fluid(s); DMEM, Dulbecco's modified essential medium; EGF, epidermal growth factor; FGFa, FGFb, fibroblast growth factor(s); 3 HT, tritiated thymidine; KGF, FGF-7, keratinocyte growth factor; MC, mesothelial cell(s); PDGF, platelet-derived growth factor; PLLF, pleural lavage fluid(s); PLM, pleural macrophage(s); PM, pleural macrophage(s); TGF- alpha , TGF-ß, transforming growth factors; TNF- alpha , tumor necrosis factor.

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Last Update: October 30, 1997