Evidence for Bladder Urothelial Pathophysiology in Functional Bladder Disorders

Table 1

Evidence for abnormal bladder urothelial cell structure and function in BPS/IC, FIC, and OAB.

Clinical condition	Bladder urothelial abnormality	Source	Reference
BPS/IC	Structural abnormalities (e.g., absence of epithelium, mucosal ulceration, mucosal ruptures, abnormal/leaky tight junctions, widening of spaces between cells, cell vacuolization, and urothelial detachment)	Tissue	Hunner 1914 [14]; Eldrup et al. 1983 [15]; Fall et al. 1985 [18]; Said et al. 1989 [16]; Lynes et al. 1990 [19]; Johansson and Fall 1990 [3], Johansson and Fall 1994 [17]; Tomaszewski et al. 2001 [5]; Rosamilia et al. 2003 [20]; Leiby et al. 2007 [21]
	Abnormal protein expression (e.g., abnormal cytokeratin expression; decreased chondroitin sulfate proteoglycans, uroplakin, zonula occludens 1, occludin, Junctional adhesion molecule-1, NK1, NK2, TRPV1, ASIC1, and 2; increased HLA-DR, E-cadherin, NFkB, claudin 2, bradykinin B1 receptor, cannabinoid receptor CB1, muscarinic receptors M3-M5, TRPV2, beta-hCG, VEGF, caveolin-1, inducible nitric oxide synthase, ICAM-1, IL1-α, and TNF-𝛼)	Tissue	Christmas and Bottazzo 1992 [29]; Liebert et al. 1993 [11]; Hurst et al. 1996 [30]; Abdel-Mageed and Ghoniem 1998 [38]; Slobodov et al. 2004 [9]; Laguna et al. 2006 [13]; Koskela et al. 2008 [33]; Freire et al. 2010 [10], Sánchez-Freire et al. 2011 [39]; Lee and Lee 2011 [36]; Lin et al. 2011 [35]; Schwalenberg et al. 2012 [37]; Logadottir et al. 2013 [34]; Homma et al. 2013 [32]
	Abnormal protein expression (e.g., specific production of a frizzled-8-related antiproliferative factor; increased induction of HLD-DR; increased E-cadherin, arylsulfatase A, phosphoribosyl-pyrophosphate synthetase associated protein 39, and SWI/SNF BAF 170; decreased tight junction proteins (including zonula occludens 1, occludin, plus claudins 1, 4, and 8), vimentin, putative tRNA synthetase-like protein, neutral amino acid transporter B, alpha 1 catenin, alpha 2 integrin, and ribosomal protein L27a; decreased secretion of HB-EGF and MMP-2)	Culture	Liebert et al. 1993 [11]; Keay et al. 2003 [23], Keay et al. 2004 [24]; Zhang et al. 2005 [41], Zhang et al. 2007 [42]; Shahjee et al. 2010 [28]
	Abnormal protein expression (e.g., decreased uroplakin and zona occludens 1 in animal model with APF)	In vivo (animal model)	Keay et al. 2012 [44]
	Functional abnormalities (e.g., increased intravesical urea absorption)	Tissue	Eldrup et al. 1983 [15]
	Functional abnormalities (e.g., increased paracellular permeability)	Culture	Zhang et al. 2005 [41]
	Functional abnormalities (e.g., increased intravesical urea absorption, increased sensitivity to intravesical potassium ions)	In vivo (humans)	Parsons et al. 1991 [7], Parsons et al. 1998 [8]
	Correlation of urothelial abnormalities with voiding symptoms (including denudation with nighttime frequency and pain)	Tissue	Tomaszewski et al. 2001 [5]
	Abnormal cell proliferation	Culture	Elgavish et al. 1997 [22]; Keay et al. 2003 [23]
	Abnormal cell signaling (e.g., Akt and/or beta catenin signaling, increased purinergic signaling, reduced Kir2.1 channel activity, increased intracellular calcium to carbachol, increased ATP release, increased p38MAPK phosphorylation/signaling, and increased p53 phosphorylation)	Culture/Tissue	Sun et al. 2001 [50], Sun et al. 2004 [48]; Tempest et al. 2004 [47]; Sun and Chai 2006 [51]; Kumar et al. 2007 [49]; Gupta et al. 2009 [54]; Shahjee et al. 2010 [28]; Kim et al. 2009 [55]; Yang et al. 2011 [57]; Shie et al. 2012 [56]
	Physiologic effects of APF (e.g., G2/M cell cycle block; regulation of transcription factor expression, phosphorylation/palmitoylation/nuclear translocation of CKAP4)	Culture	Abdel-Mageed and Ghoniem 1998 [38]; Rashid et al. 2004 [25]; Kim et al. 2007 [26]; Kim et al. 2012 [27]; Shahjee et al. 2010 [28]; Zacharias et al. 2012 [59]
Feline IC	Increased inducible nitric oxide synthase	Tissue	Birder et al. 2005 [63]
	Urothelial denudation, decreased transepithelial resistance, and increased permeability	Tissue	Lavelle et al. 2000 [62]
	Increased purinergic signaling	Culture	Birder et al. 2003 [70], Birder et al. 2004 [72]
Overactive bladder	Increased purinergic signaling	Tissue	Kumar et al. 2010 [101]
	Increased ornithine decarboxylase	Tissue	Li et al. 2009 [106]
	No difference in NGF (protein ELISA) OAB DO versus OAB non-DO	Tissue	Birder et al. 2007 [95]
	Increased polyamine and block of BK channel	Culture	Li et al. 2013 [107] and Li et al. 2009 [106]
	Increased TRPV1 signaling	Culture	Birder et al. 2013 [110]; Li et al. 2011 [112]; Liu et al. 2007 [113]
	Increased muscarinic signaling (increased intracellular calcium)	Culture	Li et al. 2013 [107]
	Decreased zonula occludens 1, occludin, claudin 4 in cells; decreased secretion of HB-EGF and MMP-2	Culture	Chai et al. 2014 (manuscript in preparation)
Transgenic urothelial restricted models	Decreased 𝛽1-integrin; Increased NGF	Tissue; Tissue	Kanasaki et al. 2013 [105]; Schnegelsberg et al. 2010 [94]