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Involvement of cyclooxygenase pathway in pathology of neurogenic bladder smooth muscle cells
Shirley Y. Godiwalla, M.D., Blake W. Palmer, M.D., Dominic Frimberger, M.D., Hsueh-Kung Lin, PhD, Bradley P. Kropp, M.D..
University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Introduction:
Cyclooxygenase (COX)-mediated arachidonic acid (AA) metabolism is a critical pathway in regulating pathophysiology of smooth muscle cells (SMCs) in the bladder. Neurogenic bladder is a direct result of congenital defect of spinal cord, spinal cord injury, or degenerative diseases. The most distinct feature of neurogenic bladders is the thickening of smooth muscle layer, which affects both architecture and function of the bladder. The goal of this study is to determine if COX-mediated prostaglandin E2 (PGE2) production can significantly contribute to elevated proliferation of SMCs observed in neurogenic bladders as a result of spina bifida.
Materials and Methods:
Primary cultures of bladder SMCs were established from pediatric cases with neurogenic bladders and normal functioning bladders. Levels of COX mRNA expression were determined by a real time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Levels of PGE2 accumulation in bladder SMCs were quantified by an enzyme immunoassay (EIA). Arachidonic acid and PGE2 stimulated bladder SMC growth was assayed by a colorimetric cell viability XTT assay. PGE2-activated signaling pathway was studied by Western blot analysis.
Results:
levels of both COX-1 and COX-2 mRNA were elevated in neurogenic bladder SMCs as compared to the normal bladder. Arachidonic acid stimulated significant increase in PGE2 production and proliferation of neurogenic bladder SMCs in cultures. Inhibition of COX-2 activity and function of a PGE2 receptor (EP4) suppressed AA and PGE2 stimulated neurogenic bladder SMC growth, respectively. In addition, PGE2 stimulated the activation of an important cell growth signaling pathway, PI3K/AKT.
Conclusion:
COX-mediated AA metabolism and subsequent PGE2 production and AKT phosphorylation are elevated in cultured neurogenic bladder SMCs as compared to those obtained from normal functioning bladders. If this pathway can be confirmed in neurogenic bladders directly from human cases, this pathway might be a therapeutic target to reverse hypertrophy of neurogenic bladders.
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