GROWTH-FACTORS IN BLADDER WOUND-HEALING

Introduction: Surgical and traumatic injuries to the bladder initiate a complex series of biological processes that result in wound healing. This process involves cellular proliferation, migration and different iation; removal of damaged tissue; and production of extracellular mat rix all of which may be controlled by growth factors. In skin, keratin ocyte growth factor (KGF) is induced following incisional injury. We h ypothesize that in bladder wound healing KGF and other growth factors are induced to modulate tissue repair. Methods: We have created a mode l of surgical bladder injury in the rodent. At 12, 24 and 48 hrs and 5 and 7 days after injury, the bladder was bisected and total RNA extra cted from the anterior or wounded half and posterior or non-wounded ha lf. Histological analysis of the bladder wound was performed with Maso n's Trichrome and immunohistochemistry against smooth muscle cr actin. RNase protection assays were performed to examine the expression of K GF, transforming growth factor (TGF)alpha and TGF beta 2 and 3 as well as the receptors for KGF and epidermal growth factor (EGF). Lastly, t he effects of the exogenous administration of KGF on the bladder was t ested on neonatal mice by daily injections of 5 mu g KGF per gram body weight for 5 days. Results: At 12 hours after injury KGF mRNA express ion in the anterior wounded bladder half and posterior non-wounded bla dder half was 8 and 6 times higher respectively, compared to unoperate d control bladders. A similar response was seen for TGF alpha, where t he 12 hour mRNA expression was 4.5 times higher in the anterior wounde d bladder half and 3.5 times higher in the posterior non-wounded bladd er half compared to unoperated control bladders. The nadir mRNA expres sion for both KGF and TGF alpha occurred at 7 days after bladder injur y and was the same as in unoperated control bladders. EGFR mRNA expres sion was similar to 2 times higher in both the anterior wounded and po sterior non-wounded bladder halves compared to the nadir levels which occurred at 24 hours after injury. TGF beta 2 and beta 3 mRNA levels d id not significantly change in either the anterior wounded or posterio r non-wounded bladder halves. Exogenous KGF stimulation resulted in a marked urothelial proliferation when compared to age matched control a nimals. Conclusion: During the early phases of bladder wound healing ( 12-24 hours post injury), mRNA for KGF and TGF alpha increased, wherea s TGF beta 2 and beta 3 and the KGFR and EGFR remain unchanged. Additi onally, exogenous KGF has a direct effect on urothelial proliferation. KGF and TGF alpha warrant further study as potential mediators of bla dder wound healing.