Dr. Bogdan Paltineanu M.D.Ph.D, Dr. Flory Revnic B. Sc (Kings College, Univ. of London) Ph.D.
NIGG ”Ana Aslan”, Bucharest
Rezumat:
Ranile cronice din cadrul diabetului reprezinta o piatra de incercare semnificativa pentru sistemul de sanatate si pentru resursele financiare. S-a investit mult timp, bani si resurse in prevenirea si tratarea acestor rani. Cu toate acestea, in ciuda acestor eforturi, ranile cronice continua sa fie o problema serioasa. Acest lucru i-a condus pe cercetatori sa se axeze mai mult catre o mai buna intelegere a organizarii moleculare si functionarii procesului normal de vindecare si cum acest process este alterat in ranile cronice din diabet. Acesta este un proces foarte complex, care se desfasoara in serii de interactiuni, integrate intre o multitudine de tipuri de celule, factori de crestere si cytokine.
In acest articol sunt discutate implicarea factorului inflamator a Oxidului Nitric (NO) si a modificarilor in metabolismul matriceal in procesul de vindecare al ranilor cronice din diabet.
Abstract
Chronic diabetic wounds present a significant challenge to healthcare providers and resources. Significant amounts of time, money and resources have gone into prevention and treatment of these wounds. However, despite these efforts, chronic wounds continue to pose a serious problem. This has led researchers to focus more on understanding the molecular organization and function of normal wound healing and how this process is altered in chronic diabetic wounds. This is a very complex process that occurs through a series of highly integrated interactions between a multitude of varying cell types, growth factors and cytokines.
In this review are discussed the implication of inflammatory factor, of NO and modification in matrix metabolism during chronic wound healing in diabetes.
Introduction:
In diabetics, wound healing interactions are disrupted and the process of
wound healing seems to be locked in a perpetual state of chronic inflammation.
In diabetic wound healing, a physiologic state consistent with decreased nitric oxide (NO) levels results, leading to an impaired inflammatory response, decreased collagen production, and decreased wound-breaking strength. (Witte et al., 2002)
Prior studies have also revealed the MMP levels are significantly elevated in chronic diabetic wounds, thus creating an imbalance in matrix breakdown and release of growth factors that are important for normal wound healing. (Lobmann et al., 2002)
Chronic diabetic wounds appear to be physiologically trapped in the inflammatory stage of wound healing and nitric oxide may promote normal healing by selectively reversing dysregulated factors (e.g.: localized ischemia, cell proliferation, MMP/TIMP ratio, growth factors/ cytokines, matrix synthesis) which prevent progression to the reepithelialization phase of wound healing.
Additionally, nitric oxide may play a larger role in diabetic foot problems as low levels of endothelial nitric oxide synthase, an enzyme responsible for nitric oxide production, is associated with bone fractures (Loveridge et al., 2002) and Charcot neuroarthropathy (La Fontaine et al., 2008).
Prior studies have shown that introduction of a NO donor can improve wound healing (Bohl-Masters et al., 2002). The mechanism(s) responsible for NO induced healing remains unclear. NO has been shown to be significantly reduced in chronic ulcers. Impaired healing of diabetic wounds is thought to be related to diminished NO production. (Witte et al., 2002)
Because the level of NO in chronic wounds is low, and elevation of NO enhances wound healing, a number of other approaches have been tried to deliver NO therapeutically.
Studies using compounds such as L-arginine (Shi et al., 2003), vitamin B12 (Bauer et al., 1998), and multivitamin therapy using a combination of folic acid, vitamin B6, and vitamin B12 (Boykin et al., 2005) have reported concomitant increases in wound tissue NO level and healing.
The latter study demonstrated that serum homocysteine, an inhibitor of NOS, is elevated in patients with chronic wounds; with multivitamin therapy, this inhibitor is decreased and associated with enhanced healing.
Both of these approaches employ systemic delivery of the compounds to raise NO, but do not involve a local targeted delivery of NO directly into the wound site. Very few investigations have sought to deliver NO directly into wounds.
For example, one study using a NO-modified polyvinyl alcohol hydrogel effectively healed cutaneous wounds in diabetic mice (Bohl-Masters et al., 2002). Increased production of extracellular matrix molecules was noted in this study, but no attempt was made to measure changes in MMP activity. Other approaches used to deliver NO to the wound have used linear polyethyleneimine/NO adducts (Bauer et al., 1998) and delivery of iNOS naked DNA via a collagen sponge (Thornton et al., 1998).
Both of these approaches reported toxic effects related to the delivery of excessive levels of NO to the wound, suggesting the need for a more finely controlled transient release of NO.
Conclusion:
The relatively longer-acting NO donor compounds,SNAP and SNOG, could potentially expose the chronic wound to longer duration of NO further increasing the wound healing potential and being present throughout more of the wound healing stages, and similar cell-permeable compounds which produce transient increases in tissue NO concentration, should provide a means of optimizing the therapeutic effect.
NO donor compounds may ultimately provide a new therapeutic tool for the treatment of diabetic foot wounds.
Preliminary studies are currently being performed examining SNOG attachment and release from both collagen-based and hydroxyapatite-based scaffolds.
The goals of these studies are to develop new types of synthetic graft materials for the treatment of diabetic skin and bone wounds respectively.
Future research will be directed toward development and optimization of these and other
NO delivery systems for the treatment of wounds and other diabetic complications
References
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