Importantly we provide mechanistic rationale for the use of

Importantly, we provide mechanistic rationale for the use of non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors such as celecoxib in the treatment and prevention of UTI in susceptible patients. We found that inhibition of COX-2 in mice reduced pyuria and prevented mucosal damage, but did not disrupt known beneficial mucosal responses, such as urothelial exfoliation and overall immune cell recruitment to the tranylcypromine (Ingersoll et al., 2008; Mulvey et al., 1998). This may explain the results of a small clinical trial that compared ibuprofen to the fluoroquinolone antibiotic ciprofloxacin in a 3-day course of treatment for UPEC UTI, and found similar improvement in clinical outcome at days 4 and 7 after initiation of therapy (Bleidorn et al., 2010). Although larger clinical trials are needed, together our studies suggest that NSAIDs do not just mask symptoms of UTI, but also affect the clinical outcome suggesting that these readily available and safe therapies could replace the use of antibiotic prophylaxis in susceptible individuals during periods of high risk, e.g. periods of sexual activity in women with coital-associated rUTI. The COX-2 inhibitor celecoxib has also been reported to enhance the sensitivity of multidrug resistant bacteria to antibiotics, providing a dual rationale for the use of this drug in conjunction with antibiotic therapy (Kalle and Rizvi, 2011). The following are the supplementary data related to this article.
Author Contributions T.J.H., T.S.S., G.C.H., W.F.S., M.C. and S.J.H. designed the experiments. A.E.S. and T.M.H. designed and supervised the clinical study. P.L.R. performed the statistical analysis of the clinical data. T.J.H., J.M.B. and D.J.S. performed the in vivo experiments. T.J.H. and J.M.B. extracted RNA and performed qRT-PCR. T.J.H. performed histopathological analysis. T.J.H. and T.E.R. performed immunofluorescence microscopy. S.vdP. performed proteomics experiments. H.M. performed in situ hybridization for Ptgs2. M.M. provided the anti-CCR2 monoclonal antibody. R.A.S. provided clodronate and PBS encapsulated liposomes. T.J.H., S.vdP., J.M.B., and D.J.S. analyzed data. T.J.H. and S.J.H. wrote the manuscript incorporating all of the authors\' editorial input.
Acknowledgments We thank Joel Schilling and Karen Dodson for helpful discussions and for critical evaluation of this manuscript. Research reported in this publication was supported by the National Institutes of Health under award numbers U01AI095542 (M.C. & S.J.H.), U01AI095473 (G.C.H.), R01DK051406 (S.J.H.), R01DK071619 (T.S.S.), K08AI083746 (T.J.H.), and F30DK096751 (D.J.S.), the Office of Research, Women\'s Health SCOR Grant P50DK64540 (S.J.H., T.M.H. & A.E.S.), and a Mucosal Immunology Studies Team ConsortiumU01AI095776 pilot grant (T.J.H. and G.C.H.) and Young Investigator Award (T.J.H.); and by the German Research Foundation (M.M.), the Swedish Research Council 7461 (G.C.H.) and the IngaBritt and Arne Lundberg Foundation (G.C.H.). These funding agencies played no role in the design or outcomes of this study and the authors were not paid by any company or agency to write this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Introduction Arsenic has been used therapeutically for more than 2400years for many different conditions (Antman, 2001). Following initial studies in China in the early 1980s (Zhou, 2012; Wang and Chen, 2008), arsenic trioxide—along with retinoic acid—has become the treatment of choice for relapsed promyelocytic leukemia, usually resulting in complete remission of this highly fatal rare disease (Soignet et al., 1998; Gallagher, 1998). Apoptosis occurs in human promyelocytic leukemia cells exposed to arsenic trioxide in laboratory studies (Iriyama et al., 2013). The idea that human breast cancer might also be treatable with arsenic arose from findings of apoptosis in human breast cancer cells exposed to arsenic trioxide (Xia et al., 2012; Wang et al., 2011; Du et al., 2012; Li et al., 2004; Chow et al., 2004). Several mechanisms have been proposed. For example, arsenic has been shown to cause induction of functional re-expression of the estrogen receptor in estrogen negative breast cancer cells, which could make them less aggressive (Du et al., 2012). Breast cancer remains a major cause of death in the United States and other countries. Mortality has reduced in the last few decades, but less so for estrogen-negative cancers (Jatoi et al., 2007).