Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis

Abstract

SUMMARY The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.

The nature of immune responses to urinary tract infections

“…However, owing to the release of reactive oxygen species and other cytotoxic products, activated neutrophils are also responsible for substantial toxicity to surrounding bladder tissue. In fact, excessive neutrophil responses — including the increased expression of cyclooxygenase 2 (COX2; also known as PTGS2) — cause inflammatory damage to the bladder tissue and predispose the bladder to persistent infections 36 . To reach bacteria in the bladder lumen, activated neutrophils cross multiple layers of epithelial cells, including the usually impermeable superficial epithelial cell layer 33 .…”

The Association between Chronic Inflammation and Recurrent Cystitis in Women

“…In a rodent model of OAB, Jang et al [27] demonstrated that intravesical cyclooxygenase (COX)-2 inhibitors can alter the expression of inflammatory modulators and cytokines in the bladder tissues improving the parameters of detrusor contraction. In mice, Hannan et al [24] found that the inhibition of COX-2 reduced pyuria and prevented mucosal damage, but did not disrupt any known beneficial mucosal responses, such as urothelial exfoliation and overall immune cell recruitment to the bladder. Moreover, these findings suggested that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors provided positive outcomes as the treatment and prevention of UTI in susceptible patients.…”

“…Severe pyuria and bladder inflammation with elevated serum IL-5 and serum and urine IL-6, the neutrophil chemokine CXCL1, and granulocyte colony-stimulating factor are predictive of chronic infection [24]. This chronic bladder inflammation manifests as both lymphonodular hyperplasia in the bladder submucosa and urothelial hyperplasia, with a lack of uroplakin expression, which is a marker for terminal differentiation, in the superficial facet cells [25].…”

Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract

“…Human and mouse studies have demonstrated that the magnitude of host immune responses has dramatic consequences for the outcome of disease (16)(17)(18)(19)(20)(21). For example, human polymorphisms in Toll-like receptor 4 (TLR4) increase susceptibility to asymptomatic carriage (16), while polymorphisms in CXCR1 and interferon regulatory factor 3 (IRF3) increase susceptibility to acute pyelonephritis (17,18).…”

“…For example, human polymorphisms in Toll-like receptor 4 (TLR4) increase susceptibility to asymptomatic carriage (16), while polymorphisms in CXCR1 and interferon regulatory factor 3 (IRF3) increase susceptibility to acute pyelonephritis (17,18). In addition, cyclooxygenase 2 is critical for establishment of chronic and recurrent urinary tract infections (UTIs) (21). Although there is clear evidence that host immune responses influence disease progression, human genetics is likely not the only factor that directs the disease course, given the statistics that a woman has a 50% chance of having a UTI in her lifetime.…”