Transgenic Mice Expressing MCP-1 by the Urothelium Demonstrate Bladder Hypersensitivity, Pelvic Pain and Voiding Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study.
Monocyte chemoattractant protein-1 (MCP-1) is one of the key chemokines that play important roles in diverse inflammatory and chronic pain conditions. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and voiding dysfunction. To facilitate IC/BPS research, we used transgenic technology to develop a novel urothelial MCP-1 secretion mouse model (URO-MCP-1). A transgene consisting of the uroplakin II gene promoter and the mouse MCP-1 coding sequence with a secretory element was constructed and microinjected. URO-MCP-1 mice were found to express MCP-1 mRNA in the bladder epithelium and MCP-1 protein in the urine, and developed bladder inflammation 24 hours after intravesical administration of a single sub-noxious dose of lipopolysaccharide (LPS). The inflamed bladders of URO-MCP-1 mice exhibited elevated mRNAs for interleukin (IL)-1ß, IL-6, substance P precursor, and nerve growth factor as well as increased macrophage infiltration. In parallel with these phenotypic changes, URO-MCP-1 mice manifested significant functional changes at days 1 and 3 after cystitis induction. These functional changes included pelvic pain as measured by von Frey filament stimulation and voiding dysfunction (increased urinary frequency, reduced average volume voided per micturition, and reduced maximum volume voided per micturition) as measured by micturition cages. Micturition changes remained evident at day 7 after cystitis induction, although these changes were not statistically significant. Control wild-type C57BL/6 mice manifested no clear changes in histological, biochemical and behavioral features after similar cystitis induction with LPS. Taken together, our results indicate that URO-MCP-1 mice are hypersensitive to bladder irritants such as LPS and develop pelvic pain and voiding dysfunction upon cystitis induction, providing a novel model for IC/BPS research.
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
Suming
S
Xu
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
Xu
X
Wang
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
Yaoqin
Y
Wang
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Psychology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, United States of America.
Susan
S
Lutgendorf
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, United States of America.
Catherine
C
Bradley
Department of Psychology, University of Iowa, Iowa City, Iowa, United States of America.
Andrew
A
Schrepf
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.|Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, United States of America.
Karl
K
Kreder
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
Michael
M
O'Donnell
Department of Urology, University of Iowa, Iowa City, Iowa, United States of America.
Yi
Y
Luo
J Urol. 2009 Oct;182(4 Suppl):1769-74
19692058
J Neurosci. 2002 Dec 15;22(24):10633-42
12486156
Ther Adv Urol. 2011 Feb;3(1):19-33
21789096
Int Urogynecol J. 2011 Aug;22(8):953-61
21487829
Int J Urol. 2014 Apr;21 Suppl 1:34-41
24807491
Mediators Inflamm. 2012;2012:358184
23049171
J Immunol. 1997 Jan 1;158(1):376-83
8977213
Brain Behav Immun. 2015 Oct;49:66-74
25771510
J Clin Invest. 1997 Nov 15;100(10):2552-61
9366570
Urology. 2016 Apr;90:56-61
26768711
Am J Physiol Renal Physiol. 2013 Jul 1;305(1):F111-22
23594826
Clin Exp Immunol. 2007 Feb;147(2):370-8
17223980
Am J Physiol Renal Physiol. 2015 Jan 15;308(2):F103-13
25209862
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):679-83
7846036
Biotechniques. 2001 Aug;31(2):256-8, 260
11515356
Int Urol Nephrol. 2010 Sep;42(3):629-35
19784793
J Virol. 2013 Mar;87(5):2376-89
23269787
J Urol. 2008 May;179(5):1857-61; discussion 1861-2
18353390
Am J Pathol. 2001 Aug;159(2):457-63
11485904
J Immunol. 2007 Jan 1;178(1):539-46
17182594
J Urol. 2015 May;193(5):1545-53
25623737
Infect Immun. 2002 Jun;70(6):3164-9
12011011
Pain. 2014 Sep;155(9):1755-61
24907404
Diabetes. 2008 Nov;57(11):3025-33
18633103
J Urol. 2002 Mar;167(3):1497-502
11832777
Urology. 2015 Jun;85(6):1454-65
26099889
J Urol. 2005 Feb;173(2):630-4
15643278
J Interferon Cytokine Res. 2009 Jun;29(6):313-26
19441883
Am J Pathol. 2002 Jun;160(6):2095-110
12057914