Suburothelial Myofibroblasts In The Human Overactive Bladder And The Effect Of Botulinum Neurotoxin Type A Treatment

Main Category: Urology / Nephrology
Article Date: 02 Feb 2009 - 4:00 PDT

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UroToday.com - A network of interstitial cell-like myofibroblasts has been identified in the lamina propria. These cells form a functional syncytium through extensive connexin43 (Cx43) gap junction coupling. By their close proximity to unmyelinated afferent nerves and the fact that their own activity is modulated by exogenous ATP (via P2Y receptors) and low pH [1-4], it is proposed that protons or local release of ATP from the urothelium generate depolarising Ca2+ waves that spread across the myofibroblasts network and that, thereby, myofibroblasts are able to integrate focal signals from different regions of the bladder wall [5-9].

Muscarinic M2 and M3 receptor labeling has also been localised to suburothelial myofibroblasts and is increased in samples from idiopathic overactive bladders; an increase in M2 receptor labeling was also seen in samples from patients with painful bladder syndrome [10]. However, isolated myofibroblasts do not respond to exogenous muscarinic receptor agonists by a rise of intracellular [Ca2+], so the intracellular signaling mechanisms remain unknown [8]. Modulating the coupling strength between the cells would influence the travel distance of the signal within the syncytium, and consequently the number of afferent fibres stimulated.

A recent animal study [11] that established a link between increased gap junction expression in lamina propria myofibroblasts and detrusor overactivity, found three times higher suburothelial cx43 immunoreactivity in rats with detrusor overactivity following spinal cord transsection. Gap junction blockade reduced spontaneity, and it was followed that spontaneous activity in the bladder requires gap junction upregulation in lamina propria myofibroblasts.

In the present study of over 20 patients with NDO and IDO, increased gap junction formation in the suburothelial myofibroblast layer has been demonstrated compared to controls with no OAB [12]. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Interestingly, the increase in Cx43 immunoreactivity in the suburothelium was not accompanied by increased numbers of c-kit positive cells, nor was there a return to normal values after BoTN/A treatment. Although BoNT/A injected into the bladder wall has been known to reduce the pathological sensation of urgency and suppress DO, suburothelial gap junction density does not seem to be altered by intradetrusor BoNT/A injections. Thus, the suppression of DO by BoNT/A is not exerted by a remodelling of the gap junction distribution, at least in the suburothelium, but altered transmitter release might influence functional properties. This would be in keeping with the known temporary (approx. 10 months) effect of BoNT/A. BoNT/A has been shown to decrease sensory P2X3 and TRPV1 receptors in suburothelial nerve fibres [13], which might represent the structural surrogate mainly affected by BoNT/A in the suburothelial space.

The authors are aware of the methodological restrictions of quantitative immunohistochemistry - the only available method to quantitatively examine the suburothelial space selectively. Slight differences in staining intensities are regarded as non-specific, due to the limited accuracy of the method. Quantification of elongated structures is particularly difficult, as their orientation in the section determines their representation either as punctate or fibre-like. Therefore, we restricted our analysis to distinct punctate staining, (ie gap junctions with a diameter of 0.1 µm [14], or scattered, easy to count c-kit positive cells). Second, we used standardised procedures for tissue processing, staining and analysis during the entire study. MF density increases toward the bladder neck [15], so we specifically took biopsies from that same area. Theoretical limitations by the size of biopsies obtained via flexible cystoscopy have been addressed in several previous studies using identical protocols [13, 16, 17], and this is likely to be the only type of tissue available for future research in this field from this department.

References:

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[17] Brady CM, Apostolidis A, Yiangou Y, Baecker PA, Ford AP, Freeman A, Jacques TS, Fowler CJ, Anand P. P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin. Eur Urol 2004; 46:247-53.

Written by Alexander Roosen, MD and Clare J. Fowler, MD as part of Beyond the Abstract on UroToday.com

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