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Airway Delivery of Silica Increases Susceptibility to Mycobacterial Infection in Mice: Potential Role of Repopulating Macrophages¹

Rajamouli Pasula^2,*, Bradley E. Britigan^*,, Joanne Turner and William J. Martin, II

^* Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267; Veterans Affairs Medical Center, Cincinnati, OH 45267; Center for Microbial Interface Biology, Division of Infectious Diseases, Department of Internal Medicine, Ohio State University, Columbus, OH 43210; and National Institutes of Health, National Institute on Environmental Health Sciences, Research Triangle Park, NC 27709

Silica exposure results in an increased lifelong risk of developing mycobacterial pulmonary infections. To date, there are no animal models that replicate this finding to permit assessment of the mechanisms underlying susceptibility to mycobacterial infection. To test the hypothesis that prior silica exposure increases risk of mycobacterial infection, we intratracheally (I.T.) administered silica, a control dust (Al₂O₃) or saline into mechanically ventilated C57BL/6 mice. Later, the mice received Mycobacterium avium or Mycobacterium tuberculosis I.T. Mice were sacrificed at defined time points and mycobacteria in lung homogenates were quantified. M. avium or M. tuberculosis infection was markedly increased in silica-exposed mice compared with mice exposed to either Al₂O₃ or saline beginning 3 wk after silica exposure. Similarly, lung sections from silica-exposed mice had many more acid fast bacilli⁺ (AFB⁺) organisms than from control mice. Alveolar macrophages (AMs) from bronchoalveolar lavage of silica-exposed mice also revealed a higher number of mycobacteria compared with mice treated with Al₂O₃ or saline. In addition, passive transfer of AMs from silica-exposed mice to control mice increased M. tuberculosis susceptibility. These results indicate that silica exposure converts mycobacteria-resistant mice into mycobacteria-susceptible mice via a process that likely involves a new population of AMs that are more susceptible to mycobacterial infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 HL076955 (to R.P. and B.E.B.) and Veterans Affairs Merit Review Award (to B.E.B.).

² Address correspondence and reprint requests to Dr. Rajamouli Pasula, Department of Internal Medicine, University of Cincinnati, PO Box 670557, Cincinnati, OH 45267-0557. E-mail address: pasular{at}ucmail.uc.edu

³ Abbreviations used in this paper: AM, alveolar macrophage; BAL, bronchoalveolar lavage; I.T., intratracheal(ly); EGFP, enhanced GFP; AFB, acid fast bacilli.