Silicosis is an inflammatory lung disease induced by the inhalation of

Silicosis is an inflammatory lung disease induced by the inhalation of silica-containing dust particles. inflammation. Results show that SNX-5422 this incidence of lung tumors in silicotic mice treated with NNK was significantly increased compared with mice exposed to silica or NNK alone. Synthetic SNX-5422 oligonucleotides (ODN) made up of repetitive TTAGGG motifs can block pathologic inflammation. We therefore examined whether treatment with these suppressive (Sup) ODN could block silica-induced pulmonary inflammation and thereby reduce susceptibility to lung malignancy. Results show that Sup (but not control) ODN inhibit pulmonary fibrosis and other inflammatory manifestations of chronic silicosis. Of greater import Sup ODN reduced lung tumor incidence and multiplicity in silicotic mice exposed to NNK. These findings establish an experimental model for examining the role of silicotic inflammation in malignancy susceptibility and demonstrate that Sup ODN symbolize a novel therapy for chronic silicosis. Introduction The World Health Organization estimates that more than 1 million workers are occupationally exposed to silica dust annually SNX-5422 in the SNX-5422 USA (1). These inhaled particles are taken up by lung macrophages scavenger receptors and trigger the production of proinflammatory cytokines [including tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β)] chemokines and reactive oxygen species (2). Patients with silicosis typically present with pulmonary infiltrates and fibrosis (3-9). Epidemiological studies suggest that silicosis increases an individual’s susceptibility to lung tumors initiated by exposure to cigarette smoke although data on this issue is usually inconsistent (10-13). The broader literature shows that inflammatory processes contribute to the development and/or progression of many types of malignancy (14). Cigarette smoke contains a number of carcinogens of which Mouse monoclonal to TrkA 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is among the most abundant and potent (15). Exposure to NNK induces the formation of DNA adducts that cause mutations in important genes including and (15 16 Although cellular genes are mutated by exposure to cigarette smoke inflammation (such as that induced by silica particles) promotes the growth of these mutagenized cells and thus supports cancer development (17-19). Limited data suggest that treatment with anti-inflammatory brokers can reduce host susceptibility to malignancy (14 20 Our group has been studying the ability of suppressive oligonucleotides (Sup ODN) SNX-5422 to downregulate pathologic inflammatory responses. These ODN express repetitive TTAGGG motifs patterned after the immunosuppressive domains present in mammalian telomeres (21). Previous studies showed that TTAGGG motifs (released by hurt host cells) block Th1 and proinflammatory cytokine production and downmodulate overexuberant/pathologic immune responses (such as those found in septic shock and autoimmune diseases) (21-26). The activity of Sup ODN is usually linked to their ability to inhibit elements of the STAT1 and STAT4 stimulatory cascades (26-28). A novel murine model was developed to explore whether Sup ODN could limit the chronic inflammation caused by silicosis and thereby reduce susceptibility to NNK-initiated lung malignancy. Silicosis similar to that observed in human miners was elicited by instilling crystalline silica into the lungs of mice (29). When these animals were exposed to NNK lung tumor multiplicity increased. This increased susceptibility to lung malignancy was reversed by treatment with Sup ODN. These findings provide the first experimental evidence that (i) silicotic inflammation increases lung malignancy susceptibility and (ii) treatment with Sup ODN can protect against this increased tumorigenesis. Materials and methods ODN and reagents Phosphorothioate ODN were synthesized at the Core Facility of the Center for Biologics Evaluation and Research facility Food and Drug Administration (Bethesda MD). The following ODN were used: suppressive ODN TTAGGGTTAGGG TTAGGGTTAGGG; control ODN TTCAAATTCAAA TTCAAATTCAAA. All ODN were free of detectable protein or endotoxin contamination. Crystalline silica (mean.