Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disease of unknown etiology. A naturally occurring disease termed feline interstitial cystitis (FIC) reproduces many features of IC/BPS patients. To gain insights into mechanisms underlying IC/BPS, we investigated pathological changes in the lamina propria (LP) of the bladder and proximal urethra in cats with FIC, using histological and molecular methods. Compared to control cat tissue, we found an increased number of de-granulated mast cells, accumulation of leukocytes, increased cyclooxygenase (COX)-1 expression in the bladder LP, and increased COX-2 expression in the urethra LP from cats with FIC. We also found increased suburothelial proliferation, evidenced by mucosal von Brunn’s nests, neovascularization and alterations in elastin content. Scanning electron microscopy revealed normal appearance of the superficial urethral epithelium, including the neuroendocrine cells (termed paraneurons), in FIC urethrae. Together, these histological findings suggest the presence of chronic inflammation of unknown origin leading to tissue remodeling. Since the mucosa functions as part of a “sensory network” and urothelial cells, nerves and other cells in the LP are influenced by the composition of the underlying tissues including the vasculature, the changes observed in the present study may alter the communication of sensory information between different cellular components. This type of mucosal signaling can also extend to the urethra, where recent evidence has revealed that the urethral epithelium is likely to be part of a signaling system involving paraneurons and sensory nerves. Taken together, our data suggest a more prominent role for chronic inflammation and tissue remodeling than previously thought, which may result in alterations in mucosal signaling within the urinary bladder and proximal urethra that may contribute to altered sensations and pain in cats and humans with this syndrome.
Highlights
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic pain syndrome characterized by suprapubic pain, and urinary frequency and urgency in the absence of an alternative explanation for the symptoms (Hanno et al, 2011)
To determine whether there was an increase in mast cells in cats with feline interstitial cystitis (FIC) compared to healthy controls, we assessed granulated and de-granulated mast cells in the lamina propria (LP) and smooth muscle (SM) of the bladder and urethral tissue (Figures 2, 3)
No significant correlation between age and number of mast cells was observed in either control or FIC cat bladder or urethrae (Pearson correlation r for bladder: −0.25 and −0.20 for control and FIC cats, respectively; for urethra: −0.07 and 0.05 for control and FIC cats, respectively). These results indicate that the bladder LP of cats with FIC contained a large number of de-granulated mast cells, consistent with findings in human tissue (Letourneau et al, 1992, 1996; Theoharides et al, 1995, 2001; Pang et al, 1996; Larsen et al, 2008)
Summary
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic pain syndrome characterized by suprapubic pain, and urinary frequency and urgency in the absence of an alternative explanation for the symptoms (Hanno et al, 2011). A number of alterations in the expression of urothelial-associated proteins (e.g., zonula occludens type 1, E-cadherin, and uroplakins; Lavelle et al, 2000; Slobodov et al, 2004; Hauser et al, 2008, 2015), receptors/ion channels (e.g., purinergic; transient receptor potential channels—TRPs), and release of transmitters (e.g., ATP, NO) from the urothelium, both basal or in response to mechanical or chemical stimuli were identified (Birder et al, 2003, 2004, 2005; Sun and Chai, 2004; Kumar et al, 2007) These alterations can contribute to the disruption of urothelial barrier and sensory functions, resulting in increased afferent nerve activity and amplified input to the CNS (Birder et al, 2004, 2010; Sun and Chai, 2004; Roppolo et al, 2005; Kumar et al, 2007), and may represent underlying mechanisms for bladder symptoms such as hypersensitivity, pain or urgency
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