Scientists at Washington University School of Medicine in St. Louis found that inhibiting COX-2, an immune protein that causes inflammation, eliminated recurrent urinary tract infections in the mice.
COX-2 is one of the proteins blocked by nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen.
"If we can confirm this link in clinical trials, many people potentially could benefit very quickly," said Thomas Hannan, DVM, PhD, research instructor in pathology and immunology. "But for now, it's important to remember that urinary tract infections are serious, and antibiotic treatment is often necessary. Patients should not treat these infections on their own without help from a medical provider."
Hannan presents the results May 18 in Boston at the general meeting of the American Society for Microbiologists.
Scientists estimate half of all women experience a urinary tract infection, the second most common type of bacterial infection, at some point in their lives. Additional recurrent infections affect 20 to 40 percent of these patients. If the infections spread to the kidneys and bloodstream, serious complications can result.
Hannan and his colleagues previously found in mouse studies that immune system overreaction to an initial infection may increase vulnerability to subsequent infections.
"We thought that the immune response was too weak in patients who kept getting urinary tract infections, but we are learning that an overly strong immune response can be just as problematic," Hannan said.
In the new study, the scientists found evidence in women and mice that immune cells known as neutrophils are significant contributors to repeat infections. In their eagerness to break into the bladder to fight infection, neutrophils leave tracks in the protective lining of the bladder's interior.
Scientists believe that excessive damage from these cells may provide footholds that let other bacteria grab hold of the bladder lining and establish severe infections.
The researchers manipulated the strength of the neutrophil response in mice to identify a "sweet spot" - not too much response and not too little - that eradicated urinary tract infection without increasing future infection risk.
The researchers found that mice with increased vulnerability to repeat infections had more inflammatory molecules in their bladder than mice that were resistant to repeat infections. When the scientists treated the mice with drugs that blocked well-known inflammatory factors, inhibitors of COX-2 dramatically reduced susceptibility both in mice with previous infections and in mice that had not been infected earlier.
When the investigators examined the effect of COX-2 inhibition on the immune response in the bladder, they found that neutrophils still came into the bladder in large numbers but caused much less damage to the protective lining. As a result, COX-2 inhibitors are able to selectively target the detrimental effects of inflammation while maintaining the beneficial responses.
"These are encouraging results, and we hope to verify the potential benefits of COX-2 inhibitors soon in a large clinical trial," said senior author Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology. Hultgren directs the Center for Women's Infectious Disease Research at Washington University.
Hannan T, Roberts PL, Riehl TE, van der Post S, Binkley JM, Schwartz DJ, Miyoshi H, Mack M, Schwendener RA, Hooton TM, Stappenbeck TS, Hansson GC, Stenson WF, Colonna M, Stapleton AE, Hultgren SJ. Inhibition Of cyclooxygenase-2 prevents chronic and recurrent bladder infection. Presented May 18, 2014, at the general meeting of the American Society for Microbiologists, Boston.
This work was supported by National Institutes of Health (NIH) grants U01 AI095542, U01 AI095473, DK51406, DK90251, K08 AI083746 and F30 DK09675, Office of Research, Women's Health SCOR Grant P50 DK64540, and a Mucosal Immunology Studies Team consortium U01 AI095776 pilot grant; and by the German Research Foundation, the Swedish Research Council 7461, and the IngaBritt and Arne Lundberg Foundation.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.