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Fibrosis underlies male lower urinary tract symptoms

Two recent studies have highlighted the importance of fibrosis in lower urinary tract symptoms (LUTS) in men and in mouse models. Fibrosis is the deposition of large amounts of collagen-rich connective tissue that can lead to organ damage. The most common symptoms vary but LUTS can involve changes or problems with urination, such as a hesitant, interrupted, weak stream; urgency and leaking or dribbling; more frequent urination, especially at night; and urge incontinence. Previous studies have suggested that deposition of fibrosis in the prostate gland contributes to the development of LUTS/BPH (benign prostatic hyperplasia) in men. The extent to which fibrosis plays a role in the pathology of LUTS remains to be defined.

In 2003, NIDDK’s Medical Therapy of Prostatic Symptoms (MTOPS) trial reported that combination therapy of two drugs (finasteride and doxazosin) is more effective than either drug singly in the treatment of BPH. Medical and surgical interventions, however, do not achieve symptom relief for all men with lower urinary tract dysfunction or may not provide a durable response. In one recent study, researchers examined tissue specimens to test the hypothesis that fibrotic changes in the prostate may be associated with an increased risk for clinical progression to more severe symptoms among MTOPS participants. The researchers reported significant alterations in the architecture of collagen (i.e., a surrogate marker for fibrosis) in prostate specimens from men who exhibited clinical progression compared to those who did not. This finding suggests that anti-fibrotic medications might offer another potential treatment option to men with BPH. Furthermore, men who had worsening symptoms were also found to have a high body mass index (a measure of weight relative to height).

In a second recent study, investigators sought to better understand the inflammation and pain associated with LUTS/BPH using a mouse model. The model is created by infection of the male mouse urethra with a strain of Escherichia coli (E. coli) bacteria called CP1; the mice then display symptomatic changes that mimic those observed in human LUTS/BPH. The investigators showed that E. coli CP1 infection increases the percentage of collagen within the prostate. Furthermore, the researchers identified that the immune system of a certain mouse strain increased production of two proteins called IL-4 and IL-13 in response to CP1 infection. These two proteins were shown to be associated with fibrosis in previous studies. Strategies that target IL-4 and IL-13 could thus be tested to see if they reduce the fibrosis and pain associated with LUTS/BPH in this model system.

Taken together, these studies report that fibrosis underlies LUTS/BPH in both humans and the CP1-induced mouse model. Further research will be required to determine whether anti-fibrotic medications can be of clinical benefit in this burdensome condition.

Macoska JA, Uchtmann KS, Leverson GE, McVary KT, and Ricke WA. Prostate transition zone fibrosis is associated with clinical progression in the MTOPS Study. J Urol 202: 1-8, 2019.

Bell-Cohn A, Mazur DJ, Hall C, Schaeffer AJ, and Thumbikat P. Uropathogenic Escherichia coli-induced fibrosis, leading to lower urinary tract symptoms, is associated with type 2 cytokine signaling. Am J Physiol Renal Physiol 316: F682-F692, 2019.

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