- Email: [email protected]
Editorial: Inducible Nitric Oxide Synthase in Wound Healing
0022-5347/04/1715-1948/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 1948, May 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000123721.71213.01
EDITORIAL: INDUCIBLE NITRIC OXIDE SYNTHASE IN WOUND HEALING Nitric oxide is a ubiquitous and important chemical mediator present in multiple organ systems, and is produced by nitric oxide synthase. This enzyme exists in 3 different isoforms.1 Neuronal (nNOS) and epithelial (eNOS) forms are 2 isoforms that are constitutively expressed and produce nitric oxide from L-arginine. The third form, the inducible isozyme (iNOS), is found only in certain circumstances. Nitric oxide has an important role in erectile function which is well known to urologists. It also has significant regulatory effects in the kidneys, vasculature and heart. The constitutively expressed enzymes nNOS and eNOS are activated via the calcium dependent calmodulin cascade. iNOS is induced by stimuli, one of which is wound healing. In this issue of The Journal Cavalcanti et al (page 1943) present an impressive series of 33 bulbar urethral strictures for which they have immunohistochemically studied the distribution of nNOS and iNOS. They demonstrate that with increasing spongiofibrosis there is a decrease in nNOS immunoreactivity and an increase in iNOS immunoreactivity. Patients with a normal bulbar urethra who had undergone penectomy were evaluated as controls, all of whom had normal nNOS immunoreactivity and the absence of iNOS. The expression of iNOS in the strictures was predominately localized to the urothelium. The degree of spongiofibrosis was measured by calculating the ratio of smooth muscle-tocollagen in the entire cross-sectional area of the diseased urethra. With increasing spongiofibrosis there was loss of smooth muscle, increased collagen deposition and loss of nNOS with the appearance of iNOS immunoreactivity. Nerve fibers demonstrated by S-100 staining were unchanged. The authors conclude that urethral strictures demonstrate fibrotic processes associated with significant changes in nitric oxide synthase activity. They further hypothesize that the functional nerve supply to the urethral spongiosum may be critical to the maintenance of its function (ie nNOS activity) and that abnormal collagen synthesis following urethral trauma may be stimulated by inappropriate iNOS activity. One of the most interesting aspects of this hypothesis and of wound healing in general is whether the body’s repair mechanisms are protective and/or detrimental to the organ system. The role of nitric oxide synthase has been studied extensively in the healing of cutaneous wounds.2 Wound healing of the skin follows multiple sequential events beginning with an inflammatory phase, a reparative phase and a contractile phase. iNOS has been found to be expressed in keratinocytes,
fibroblasts, Langerhans’ cells and endothelial cells in the skin during wound healing. It is expressed by macrophage during the early inflammatory phase of repair. Its role in fibroblasts is believed to regulate collagen synthesis. iNOS is involved not only in providing the tensile strength of the wound, but also in the proliferation of the skin keratinocytes. iNOS knock-out mice demonstrate delayed wound healing as do animals treated with nitric oxide synthase inhibitors.3, 4 Inhibition of iNOS also results in impaired re-epithelialization of the wound. iNOS expression has been found in pathological inflammatory conditions of the skin, such as psoriasis.5 With regard to urethral strictures, many questions about the healing of the urethra, the pathophysiology of spongiofibrosis and the importance of the normal repair mechanisms remain to be elucidated. This study certainly illustrates a potential area of further investigation into the mechanisms of healing in the urethra and suggests a potential therapeutic strategy to inhibit spongiofibrosis. Normal re-epithelialization to preserve the epithelial lining of the urethra while blocking the fibrosis and contraction of the spongiosum would be necessary for this to be successful. There remains a need for better understanding of the normal repair mechanisms of the urethra as well as the benefits and consequences of impairing them.
1948
J. Christopher Austin Department of Urology University of Iowa Iowa City, Iowa REFERENCES
1. Alderton, W. K., Cooper, C. E. and Knowles, R. G.: Nitric oxide synthases: structure, function, and inhibition. Biochem J, 357: 593, 2001 2. Frank, S., Kampfer, H., Wetzler, C. and Pfeilschifter, J.: Nitric oxide drives skin repair: novel function of an established mediator. Kidney Int, 61: 882, 2002 3. Yamasaki, K., Edington, H. D., McClosky, C., Tzeng, E., Lizonova, A., Kovesdi, I. et al: Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest, 101: 967, 1998 4. Stallmeyer, B., Kampfer, H., Kolb, N., Pfeilschifter, J. and Frank, S.: The function of nitric oxide in wound repair: inhibition of inducible nitric oxide-synthase severely impairs wound reepithelialization. J Invest Dermatol, 113: 1090, 1999 5. Bruch-Gerharz, D., Fehsel, K., Suschek, C., Michel, G., Ruzicka, T. and Kolb-Bachofen, V.: A proinflammatory activity of Interleukin 8 in human skin: expression of inducible nitric oxide synthase in psoriatic lesions and cultured keratinocytes. J Exp Med, 184: 2007, 1996
Vol. 171, 1948, May 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000123721.71213.01
EDITORIAL: INDUCIBLE NITRIC OXIDE SYNTHASE IN WOUND HEALING Nitric oxide is a ubiquitous and important chemical mediator present in multiple organ systems, and is produced by nitric oxide synthase. This enzyme exists in 3 different isoforms.1 Neuronal (nNOS) and epithelial (eNOS) forms are 2 isoforms that are constitutively expressed and produce nitric oxide from L-arginine. The third form, the inducible isozyme (iNOS), is found only in certain circumstances. Nitric oxide has an important role in erectile function which is well known to urologists. It also has significant regulatory effects in the kidneys, vasculature and heart. The constitutively expressed enzymes nNOS and eNOS are activated via the calcium dependent calmodulin cascade. iNOS is induced by stimuli, one of which is wound healing. In this issue of The Journal Cavalcanti et al (page 1943) present an impressive series of 33 bulbar urethral strictures for which they have immunohistochemically studied the distribution of nNOS and iNOS. They demonstrate that with increasing spongiofibrosis there is a decrease in nNOS immunoreactivity and an increase in iNOS immunoreactivity. Patients with a normal bulbar urethra who had undergone penectomy were evaluated as controls, all of whom had normal nNOS immunoreactivity and the absence of iNOS. The expression of iNOS in the strictures was predominately localized to the urothelium. The degree of spongiofibrosis was measured by calculating the ratio of smooth muscle-tocollagen in the entire cross-sectional area of the diseased urethra. With increasing spongiofibrosis there was loss of smooth muscle, increased collagen deposition and loss of nNOS with the appearance of iNOS immunoreactivity. Nerve fibers demonstrated by S-100 staining were unchanged. The authors conclude that urethral strictures demonstrate fibrotic processes associated with significant changes in nitric oxide synthase activity. They further hypothesize that the functional nerve supply to the urethral spongiosum may be critical to the maintenance of its function (ie nNOS activity) and that abnormal collagen synthesis following urethral trauma may be stimulated by inappropriate iNOS activity. One of the most interesting aspects of this hypothesis and of wound healing in general is whether the body’s repair mechanisms are protective and/or detrimental to the organ system. The role of nitric oxide synthase has been studied extensively in the healing of cutaneous wounds.2 Wound healing of the skin follows multiple sequential events beginning with an inflammatory phase, a reparative phase and a contractile phase. iNOS has been found to be expressed in keratinocytes,
fibroblasts, Langerhans’ cells and endothelial cells in the skin during wound healing. It is expressed by macrophage during the early inflammatory phase of repair. Its role in fibroblasts is believed to regulate collagen synthesis. iNOS is involved not only in providing the tensile strength of the wound, but also in the proliferation of the skin keratinocytes. iNOS knock-out mice demonstrate delayed wound healing as do animals treated with nitric oxide synthase inhibitors.3, 4 Inhibition of iNOS also results in impaired re-epithelialization of the wound. iNOS expression has been found in pathological inflammatory conditions of the skin, such as psoriasis.5 With regard to urethral strictures, many questions about the healing of the urethra, the pathophysiology of spongiofibrosis and the importance of the normal repair mechanisms remain to be elucidated. This study certainly illustrates a potential area of further investigation into the mechanisms of healing in the urethra and suggests a potential therapeutic strategy to inhibit spongiofibrosis. Normal re-epithelialization to preserve the epithelial lining of the urethra while blocking the fibrosis and contraction of the spongiosum would be necessary for this to be successful. There remains a need for better understanding of the normal repair mechanisms of the urethra as well as the benefits and consequences of impairing them.
1948
J. Christopher Austin Department of Urology University of Iowa Iowa City, Iowa REFERENCES
1. Alderton, W. K., Cooper, C. E. and Knowles, R. G.: Nitric oxide synthases: structure, function, and inhibition. Biochem J, 357: 593, 2001 2. Frank, S., Kampfer, H., Wetzler, C. and Pfeilschifter, J.: Nitric oxide drives skin repair: novel function of an established mediator. Kidney Int, 61: 882, 2002 3. Yamasaki, K., Edington, H. D., McClosky, C., Tzeng, E., Lizonova, A., Kovesdi, I. et al: Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Invest, 101: 967, 1998 4. Stallmeyer, B., Kampfer, H., Kolb, N., Pfeilschifter, J. and Frank, S.: The function of nitric oxide in wound repair: inhibition of inducible nitric oxide-synthase severely impairs wound reepithelialization. J Invest Dermatol, 113: 1090, 1999 5. Bruch-Gerharz, D., Fehsel, K., Suschek, C., Michel, G., Ruzicka, T. and Kolb-Bachofen, V.: A proinflammatory activity of Interleukin 8 in human skin: expression of inducible nitric oxide synthase in psoriatic lesions and cultured keratinocytes. J Exp Med, 184: 2007, 1996