Specialized proresolution mediators in the bladder: annexin-A1 normalizes inflammation and bladder dysfunction during bladder outlet obstruction

Abstract

Bladder Outlet Obstruction (BOO) is ultimately experienced by ≈90% of men, most commonly secondary to benign prostatic hyperplasia. Inflammation is a critical driver of BOO pathology in the bladder and can be divided into two critical steps; initiation and resolution. While great strides have been made toward understanding initiation of inflammation in the bladder (through the NLRP3 inflammasome), no studies have examined resolution. Resolution is controlled by 5 classes of compounds known as Specialized Pro-resolving Mediators (SPMs), all of which bind to one or more of 7 different receptors. Using immunocytochemistry, we show the presence of 6 of the known SPM receptors in the bladder of control and BOO rats; the 7th has no rodent homolog. The expression was predominantly localized to the urothelia, often with some expression in the smooth muscle, but little to none in the interstitial cells. We next examined the therapeutic potential of the Annexin-A1 resolution system, also present in control and BOO bladders. Using the peptide mimetic Ac2-26, we blocked inflammation-initiating pathways (NLRP3 activation), diminished BOO-induced inflammation (Evans blue dye extravasation), and normalized bladder dysfunction (urodynamics). Excitingly, Ac2-26 also promoted faster and more complete functional recovery after surgical de-obstruction. Together, the results demonstrate that the bladder expresses a wide variety of potential pro-resolving pathways and that modulation of just one of these pathways can alleviate many detrimental aspects of BOO and speed recovery after de-obstruction. This work establishes a precedent for future studies evaluating SPM effectiveness in resolving the many conditions associated with bladder inflammation.

Specialized pro-resolution mediators in the bladder: Receptor expression and recovery of bladder function from cystitis

“…32 Recently, we expounded on a possible role for Annexin-A1 in treating BOO using a rat model. 33 In those studies, we demonstrated the presence of all six SPM receptors in the rat bladder. Expression was predominantly urothelial with some expression in the detrusor and some changes in expression pattern in response to BOO.…”

“…We began these studies by examining the repertoire of SPM receptors expressed in the mouse and human bladder. While our previous work documented expression in rat bladder 33 expression needed to be confirmed in these species. Our results show expression of all known SPM receptors in the bladder in both species (six in mice, seven in humans).…”

“…Recently, we showed the presence of various SPM receptors in the control rat bladder, some of which changed expression pattern in response to BOO. 33 Before initiating studies in the mouse, we sought to confirm expression of these SPMs in the bladder of this species and so we have performed immunocytochemistry for all the various SPM receptors on mouse bladders (Figure 2). Likewise, to determine if the investigated pathways may be relevant in humans, we have also stained sections of human bladder (Figure 3).…”

“…This is only the second paper to explore this field, define the potential pathways present and test individual SPMs for beneficial activity. In our previous manuscript, 33 we assessed the effects of one SPM, Annexin-A1, on BOO in rats and found it to be quite effective in promoting the resolution of inflammation and restoring normal bladder function. In this study, we expand that work to examine three additional SPMs, each representative of a class of the lipid-based mediators.…”

“…This initial work demonstrates the ability of the urothelia to respond to three additional classes of SPMs, the resolvins, the maresins and the protectins, in addition to the previously identified Annexin-A1. 33 Annexin-A1 binds to FPR2 to exert its pro-resolution activity, whereas RvE1 acts through CHEMR23 and BLT-1. 66 The positive response to RvE1 suggests that at least one, if not both, of these receptors can be activated in urothelia.…”