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Urologic Diseases Research Updates
Winter 2011

Study Uncovers Pain Pathway Associated with Urinary Tract Infections

Photo of an albino lab mouse.

A study by scientists at Northwestern University helps explain how urinary tract infections (UTIs) cause pelvic pain. The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and offers insight into new UTI pain management strategies.

UTIs trigger more than 7 million trips to the doctor and more than 100,000 trips to the emergency room each year. “Although most patients with UTI experience pelvic pain, the precise mechanism underlying UTI-induced pelvic pain remains unknown,” wrote David J. Klumpp, Ph.D., associate professor of urology at Northwestern University’s Feinberg School of Medicine, and co-authors.

Whereas the vast majority of UTIs cause a painful, burning sensation in the bladder and urethra, about 5 percent of UTI patients have no symptoms. To learn more about UTI pain mechanisms, Klumpp and colleagues looked for clues in the bacteria that fail to cause symptoms when they infect the urinary tract.

The researchers used a laboratory mouse model to study UTI-associated pelvic pain. Mouse bladders were infused with specific strains of E. coli bacteria or purified bacterial components. Pain was assessed by measuring the response to von Frey filaments—stiff, hairlike fibers—pushed against the skin over the mouse’s pelvic region. Pain receptors in skin over the pelvic region correspond to pain receptors in pelvic organs. The researchers interpreted a higher mean response frequency as an indication of greater pain.

As expected, NU14, an E. coli strain highly representative of those most commonly associated with human UTIs, elicited greater pain in mice than did 83972 E. coli, a strain that causes asymptomatic UTI in humans. Once validated, the mouse model was used to look for functional and structural differences between NU14 and 83972 E. coli.

Pain did not correlate with bladder inflammation. “Inflammation is often assumed to underlie infection pain, but we failed to observe a consistent relationship between pain and inflammation,” wrote Klumpp, et al. After bladder instillation of NU14 or 83972 E. coli, the scientists measured myeloperoxidase (MPO) levels as a marker of inflammation. MPO is a pro-inflammatory enzyme released by immune cells called neutrophils in response to the presence of bacteria. Although pain was much higher in mice infected with the NU14 strain, MPO levels were similar.

The researchers also looked at inflammation caused by mast cells, a type of immune cell that triggers inflammation when activated by bacterial pathogens. The researchers’ previous work showed that mast cells play a critical role in pain associated with interstitial cystitis, a non-pathogenic painful bladder condition. Mast cell-deficient mice tested with the UTI model, however, still showed significant pain with NU14 E. coli infection. The observation suggested to the researchers that UTI pain differs from mast cell-independent interstitial cystitis pain.

Next, the researchers looked at virulence factors, essentially the tools a bacterium uses to infect host cells. The NU14 strain has hairlike follicles called pili on its cell surface that it uses to attach to and infect host cells. By contrast, the 83972 strain lacks pili. But even when genetically endowed with the same pili as NU14, the 83972 strain did not cause pain in mice. Disabling the adhesion protein on the pilus tip of the NU14 strain that is critical for host cell attachment provided further support that pili are not key elements of UTI pain inducement. NU14, with or without a functional adhesion protein, evoked pain.

A different virulence factor, however, did mediate UTI-related pain. Lipopolysaccharide (LPS) is a structural component of the E. coli bacterial membrane. Infected hosts identify LPS as a toxin and quickly mount an immune response. Klumpp and colleagues tested their mouse model with LPS purified from NU14 and 83972 E. coli. Whereas instillation of 83972 LPS caused no pain, significant pain was evoked with instillation of NU14 LPS.

To further characterize the role of LPS in UTI pain, the researchers investigated whether pain would be inhibited in the absence of toll-like receptor 4 (TLR4)—a receptor protein found on many types of cells, including bladder cells, that binds LPS. Compared with controls, genetically modified TLR4-deficient mice experienced significantly less pain when their bladders were instilled with NU14-derived LPS.

“Our results show that LPS isolated from NU14 induced pelvic pain through a TLR4-dependent mechanism, providing a novel pathway of pelvic pain induction and relief,” wrote Klumpp, et al. “Furthermore, our study is the first, to our knowledge, to demonstrate that LPS is the initiator of UTI-induced pelvic pain.”

Interestingly, 83972-derived LPS weakened NU14 LPS-induced pelvic pain by 40 percent. The researchers speculated that 83972 LPS blocks NU14 LPS from binding to TLR4.

“These observations suggest a novel treatment strategy using a probiotic that would minimize the symptoms of infection without reliance on empirical therapies that contribute to antimicrobial resistance,” wrote Klumpp, et al. Probiotics are microorganisms with beneficial health properties, such as the bacteria in yogurt. The report called for additional research into probiotic therapies for UTIs.

To learn more about NIDDK-funded urologic research, visit www2.niddk.nih.gov/Research/ScientificAreas/Urology.

The National Kidney and Urologic Diseases Information Clearinghouse has fact sheets and easy-to-read booklets about UTI and other urologic conditions. For more information or to obtain free copies, visit www.urologic.niddk.nih.gov.

NIH Publication No. 11–5743
January 2011

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The National Kidney and Urologic Diseases Information Clearinghouse is a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

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