There is a consensus that inflammation is a causative or exacerbating factor in virtually all benign urological conditions, which we call urological conditions with an inflammatory component (UCICs; Fig. 1). The bladder has well-developed and conserved machinery in place (particularly involving the NLRP3 inflammasome) that responds to all these disparate challenges by promoting inflammation. This inflammation contributes to bladder dysfunction and, if it remains unresolved, to pathological changes such as denervation, fibrosis and smooth muscle hypertrophy. When these effects reach an irreversible state, they can vastly complicate the physician’s ability to manage these conditions. Targeting such pathways can prevent detrimental changes but suppressing the inflammatory capacity has the potential to create immunosuppressed patients and increases the risk of urinary tract infection. Moreover, patients typically present late in disease progression when tissue damage has already occurred.

Figure 1. Inflammation is a causative or exacerbating factor in virtually all UCICs. Listed with inward pointing arrows are conditions known to have an inflammatory component. For those underlined, the NLRP3 inflammasome has been shown to play a major role in triggering this inflammation. Inflammation leads to bladder dysfunction (overactive or underactive bladder) and 3 major physiological changes, fibrosis, denervation and smooth muscle hypertrophy (although not all changes are found in all conditions, eg diabetes). Ultimately such changes can lead to decompensation and end-stage bladder dysfunction.

Figure 2. Inflammation is a balance of initiating and resolving influences. Initiation of sterile inflammation is primarily controlled by damage (or danger) associated molecular patterns (DAMPs) whereas infectious inflammation is triggered by pathogen associated molecular patterns (PAMPs). These DAMPs and PAMPs function through stimulating the formation of a multimeric inflammasome complex which activates caspase-1 and ultimately releases the pro-inflammatory cytokines IL-1β and IL-18. Counterbalancing initiation is resolution, which is promoted by SPMS binding to SPM receptors. There are 5 major classes of SPMs, all of which bind to only 7 SPM receptors. SPMs function to restrain and resolve inflammation on multiple fronts such as inhibiting initiation pathways, reducing proliferation of immune cells, promoting efferocytosis, reducing neutrophil migration, etc.

Figure 3. Resolvin E1 (RvE1), maresin-1 (MaR1) and protectin D1 (PD1) reduce CP-induced in vivo bladder inflammation, as measured by the Evans blue dye extravasation assay. CP was administered at 150 mg/kg on day 0. RvE1, MaR1 or PD1(25 μg/kg) was administered on days 1, 2 and 3. On day 4, the mice were injected (intravenously) with Evans blue (25 mg/kg). One hour later bladders were extracted in formamide and absorbance (620 nm) measured. ***p < 0.001 compared to control. Hughes FM Jr, Allkanjari A, Odom MR, Jin H, Purves JT. Specialized pro-resolution mediators in the bladder: receptor expression and recovery of bladder function from cystitis. Reprinted with permission of SAGE Publications. Exp Biol Med. 2022;247(8):700-711. Copyright 2022 SAGE Publications.

Resolving inflammation was once thought to be a passive process, but it is now understood that it involves numerous endogenous and interrelated pathways.^1,2 These pathways serve as a counterbalance to the activation pathways of inflammation (Fig. 2). Specialized Proresolution mediators (SPMs) are grouped in 5 classes, 1 a protein (annexin-A1) and the other 4 (lipoxins, resolvins, maresins and protectins) are lipids derived from omega-6 or omega-3 fatty acids. The potential of these molecules to treat existing inflammation in a vast number of different conditions has spawned a new field known as resolution pharmacology. Prior to this work only 1 study (on annexin-A1) had addressed the potential of targeting these ­resolution pathways to relieve the detrimental effects of benign urological disorders.³

Our investigation found that all 7 known SPM receptors were present in both the human and mouse bladders, with expression mostly in the urothelia and detrusor. As proof that SPMs would have direct effects on bladder cells, we showed that representatives of 3 separate classes of the lipid SPMs (resolvin E1, maresin-1 and protectin D1) were highly effective at promoting in vitro wound repair of a urothelial cell monolayer. We next showed the efficacy of these 3 molecules in vivo by demonstrating that each could resolve bladder inflammation in a well-established and widely used model; the cyclophosphamide (CP)-induced hemorrhagic cystitis model (Fig. 3). In this model the SPM was given for 3 days after the establishment of inflammation (ie 1 day after CP). Focusing on resolvin E1, we found that this SPM could completely reverse bladder dysfunction (Fig. 4). Resolvin E1 also reversed signs of fibrosis (expression of TGF-β and collagen I) and one of the exciting prospects of SPMs is that they appear to promote the regression of fibrosis.^4,5

Figure 4. RvE1 restores urodynamics parameters following CP treatment. Following the treatment paradigm discussed in Figure 3, mice were subjected to urodynamics. A, average voided volume B, voiding Frequency. *p < 0.05, **p < 0.01 compared to control. Hughes FM Jr, Allkanjari A, Odom MR, Jin H, Purves JT. Specialized pro-resolution mediators in the bladder: receptor expression and recovery of bladder function from cystitis. Reprinted with permission of SAGE Publications. Exp Biol Med (Maywood). 2022;247(8):700-711. Copyright 2022 SAGE Publications.

These results are the first to find proresolution pathways in the bladder and to demonstrate the potential of the large and rapidly developing field of resolution pharmacology to treat the numerous and disparate UCICs.⁶ There is great hope that such treatments can not only normalize voiding issues, but may reverse debilitating pathological changes, such as fibrosis, that were once thought to be irreversible.