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Inflammation and growth factor expression in lung tissue of F344 rats exposed to Libby amphibole asbestos
Citation:
Padilla, D. J., M. SCHLADWEILER, U. P. KODAVANTI, J. H. Shannahan, A. Bern, H. Lowers, G. Meeker, AND S. H. GAVETT. Inflammation and growth factor expression in lung tissue of F344 rats exposed to Libby amphibole asbestos. Presented at American Thoracic Society Annual meeting, New Orleans, LA, May 14 - 19, 2010.
Impact/Purpose:
This abstract gives an update on research progress on acute pulmonary toxicological effects of Libby asbestos vs. amosite asbestos as a positive control, focusing on the expression of cytokines and growth factors which might be important in the mechanism of response.
Description:
Rationale: An increased incidence of asbestos-related diseases (ARD) in Libby, Montana has prompted toxicological investigations into the potential mechanism(s) of Libby amphibole (LA) asbestos that induce ARD. Asbestos exposure, in general, results in a potent pulmonary inflammatory response which stimulates cell proliferation and fibrosis of the lung. We hypothesized that the F344 rat would demonstrate an increase in mRNA expression of inflammatory cytokines, hemeoxygenase-I (HO-l), and growth factors in the lung after a single exposure to LA and Amosite (Amo; positive control) asbestos. Methods: Water elutriation was conducted to prepare a rat respirable fraction of LA and Amo equivalent to airborne particulate matter x 2.5 lim mass median aerodynamic diameter (PM2.5). Male F344 rats (~250 g) were exposed to a single bolus (250 ul) ofeither saline (SAL), amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal instillation (n = 6/group). Real-Time Polymerase Chain Reaction (RT-PCR) was used to evaluate the time-course of inflammation (cytokines and HO-l) and growth factor expression in the accessory lung lobe from rats euthanized at ld, 3d, 7d, 2wk, and 3mo after exposure. Results: Interleukin (lL-l) expression was unchanged among the groups at all timepoints, but both the high dose LA and Amo groups exhibited increased tumor necrosis factor-alpha (TNF-a) expression by ~2-fold at ld when compared to SAL. Interleukin-6 (lL-6) was increased in the high-dose LA and Amo at ld by ~15 and 25-fold, respectively, and at 7d, both groups were 2-fold higher than SAL. HO-l expression in the Amo group was increased at l d and 7d by 7-and 2-fold, respectively, whereas the high-dose LA group exhibited higher mRNA expression at ld, 7d, and 3mo (2 to 3-fold increase) compared to SAL. The growth factors (platelet-derived growth factor-A polypeptide, connective tissue growth factor, and ProCollagen I) were unchanged in the exposed groups with respect to SAL at all timepoints, but transforming growth factor-l beta (TGF-l~) appeared down-regulated at 3mo in all asbestosexposed groups. Conclusions: Amo and LA induced an acute inflammatory cytokine and HO-l mRNA response (up to 7d) which subsided by 2wk. However, except for down-regulation of TGF-l~ at 3mo, growth factor mRNA expression was not changed up to 3mo after exposure. Future studies will examine these inflammatory and growth factor responses to these two types of asbestos using immunohistochemical analysis to evaluate the distribution of inflammation and potential mechanisms of fibrosis. Funding: EPA/UNC CR833237. A