Diabetes Leading to an Extension of the Inflammatory Stage of Repair - Coursework Example

A Critical review of diabetes leading to an extension of the inflammatory stage of repair, thus contributing to a delay in the healing process In medical terminology, a break in the epithelial integrity of the skin is defined as a wound (Enoch and Price, 2004) while a chronic or nonhealing wound is one that does not heal in a timely fashion. (Levine, 2002) Causative factors of ulceration could be neuropathic (as, for example, due to diabetes), neoplastic, infectious, vascular or iatrogenic (e.g., due to drugs), besides others. Diabetes is a chronic systemic disorder of glucose metabolism. It is a worldwide health problem and particularly widespread in the UK (World Health Organization 2006, Department of Health 2006b). Diabetes, which is an endocrine disorder, is caused when the cells of the pancreas are unable to produce insulin or there is a deficiency of insulin within the body (WHO 2006). Diabetic foot ulcer is a major complication of diabetes. According to Bowering (2001), foot ulcers in diabetic patients are common and frequently lead to lower limb amputation unless a prompt, rational, multidisciplinary approach to therapy is taken. Diabetic wounds have been described as “complex microcosms of multiple patho-physiologic processes” (Al-Watban et al., 2007, p72 ), and are predominantly characterized by polymicrobial infection, peripheral neuropathy, structural deformity, altered immune function or increased susceptibility to infection, decreased wound nitric oxide (NO) production, and often, hypoxia/ischaemia. Hence, it is important for podiatrists who are involved with wound care management to have a proper understanding of the functional relationships of the biological processes of normal compared to pathological and non-healing ulcers in order to be able to devise treatment strategies. They also need to be aware of all the factors that influence the process of wound healing especially in diabetic ulcers. The degree of metabolic control, the presence of ischaemia or infection, and continuing trauma to feet from excessive plantar pressure are some of the factors that affect development and healing of diabetic patients' foot ulcers. The science of wound healing: normal healing According to Grey et al. (2006), most wounds, regardless of aetiology, heal without difficulty. But, at times, certain local and systemic factors can impede healing of the wound. For example, local factors such as inadequate blood supply, poor venous drainage, infection, foreign body reactions, wound dehiscence can delay wound healing. Some of the systemic factors that hinder wound healing are advancing age, systemic malignancy, chemo- and radiotherapy, impaired macrophage activity and malnutrition (Grey et al., 2006). Significant advances have occurred in understanding the science of wound healing. Acute wounds normally heal in a very orderly and efficient manner characterized by four distinct, but overlapping phases: haemostasis, inflammation, proliferation and remodelling(or maturational) phase (Diegelmann and Evans, 2004). The healing cascade begins the moment the tissue is injured. In brief, as described by Diegelmann and Evans (2004), the inflammatory phase, characterized by haemostasis and inflammation, is initiated by collagen, exposed during wound formation, which activates the clotting cascade. The first response cells, the platelets, come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and multiple cytokines , including epidermal growth factor (EGF), fibronectin, fibrinogen, histamine and platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-ß) which help in the clot formation and stabilising of the wound. This is followed by vasodilation promoted by the release of histamine from basophils. Histamine also increases the permeability of the capillary wall, allowing macromolecules, such as neutrophils, monocytes (macrophages) and plasma proteins, to leave the blood vessel. Following haemostasis, the critical task of phagocytosis is started by the neutrophils which are the second response cells to migrate to the wound site. The chemotaxis of neutrophils is initiated by PDGF. Neutrophils are responsible for the removal of foreign materials, damaged tissue, and also bacterial destruction through the formation of oxidative agents such as hydrogen peroxide and superoxide. The leucocytes and the macrophages (monocytes) are the other cells present in the wound. The macrophage secretes several enzymes (e.g., collagenases) and cytokines that help in the process of tissue reconstruction, i.e., the proliferative phase. Epithelialisation, angiogenesis, granulation tissue formation, and collagen deposition are the principal steps in the proliferative phase. In the final phase of wound healing, which is the maturational phase, the wound undergoes contraction and forms a scar. Thus, wound healing involves a complex interaction of cells and cytokines working in concert. Delayed healing of wounds Chronic wound healing does not follow the same pattern as that of normal acute wounds. In fact, in pathological conditions such as non-healing pressure ulcers, the efficient and orderly process decribed above is lost (Diegelmann and Evans, 2004 ), and the normal process of healing is disrupted in a chronic wound at one or more points in the phases of haemostasis, inflammation, proliferation and remodelling. It is commonly observed that the non-healing ulcers are locked into a state of chronic inflammation characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes, and the process of healing proceeds only after the inflammation is controlled (Diegelmann and Evans, 2004 ). Pathophysiological abnormalities that may predispose one to the formation of chronic wounds such as leg ulcers, foot ulcers, and pressure sores include compromised tissue perfusion as a consequence of impaired arterial supply (peripheral vascular disease) or impaired venous drainage (venous hypertension) and metabolic diseases such as diabetes mellitus (Bowler et al., 2001). A chronic non-healing wound exhibits an imbalance between tissue deposition stimulated by growth factors, and tissue destruction mediated by proteases, with the imbalance favoring the destructive processes. It has a biochemical environment that shows evidence of excessive inflammatory cytokines and proteases and low levels of growth factors (Barr, http://www.vnaa.org/vnaa/g/?h=html/wound_center_aug). Abnormally elevated protease levels are a concern in wound care because their uncontrolled protein-degrading activity destroys growth factors and their receptors, inhibits angiogenesis, and breaks down granulation tissue resulting in tissue damage. As has already been mentioned in the section on normal healing, growth factors or cytokines, such as platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), play a significant role in normal wound repair e.g., in cell migration, extracellular matrix formation and so on. Hence, the degradation of growth factors by proteases will result in delayed wound healing. The most predominant protease activity in chronic wounds is the neutrophil- derived elastase (Barr, http://www.vnaa.org/vnaa/g/?h=html/wound_center_aug). Wound healing in diabetes: affected key events in the inflammation phase Ineffective healing of wounds is a serious problem in diabetes, contributing to increased morbidity (Pearl and Kanat, 1988). The typical signs of inflammation are not often manifested in the wound of a patient with diabetes. The compensatory vasodilation response is limited because of the rigidity of the thickened basement membrane of the capillary endothelium (Renwick et al., 1998). Patients with diabetes experience more wound-healing problems than those without. Besides, patients with diabetes are five times more susceptible to fungal and bacterial infections (Axelrod, 1985). With poor glycaemic control, an enzyme called aldose reductase converts abnormal amounts of glucose to sorbitol, which accumulates within cells, leading to osmotic movement of water into the cell, swelling and tissue damage (Green, 1985). Also, when hyperglycaemia is not corrected, the patient becomes catabolic, breaking down protein and fat stores for energy, as glucose is not available to the cells. And, a catabolic state does not promote healing (King, 2001). The delay in wound healing observed in diabetes has been attributed to several factors. They include: 1. The endogenous production of nitric oxide (NO), which plays an important role in inflammation, tissue repair, and microvascular homoeostasis, but is significantly reduced in the wounds of diabetic patients with poor or absent ulcer healing as compared to patients with healed ulcers or non-diabetic controls (Boykin et al., 1999). 2. Cellular dysfunction in diabetic wound healing has been shown to involve both delayed infiltration of the wound with inflammatory cells (Fahey et al., 1991) and defective neutrophil function (Mowat and Baum, 1971). Fahey et al. (1991) undertook a study to determine the relationship between diabetic healing and altered polymorphonuclear (PMN) neutrophil influx by measuring tumour necrosis factor (TNF) and interleukin (IL)-6 in wound chambers implanted subcutaneously in diabetic and control mice. The study revealed that the initial inflammatory responses were similar in the two groups but the number of white blood cells and IL-6 levels were decreased towards the end of the inflammatory phase in diabetic mice. 3. The formation of advanced glycation end products (AGEs) is another important pathophysiological mechanism in the development of diabetic complications. Intracellular AGE formation leads to quenching of nitric oxide and impaired function of growth factors (Huijberts et al., 2008, p S19). 4. Several growth factors / cytokines are known to enhance wound healing. The most studied among them are platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor-ß1, and epidermal growth factor (EGF) (Singer and Clark, 1999). Patients with diabetes have impaired leucocyte function, and the metabolic abnormalities of diabetes lead to inadequate migration of neutrophils and macrophages to the wound, along with reduced chemotaxis (Delamaire et al., 1997). Such cellular changes would predispose individuals to an increased risk of wound infection. Wound infection has indeed been found to be a major complication in diabetic patients (Ferringer and Miller, 2002). However, little is known about the biology of infections in diabetic wounds, and there are no suitable animal models. No large animal studies have been performed, since there is no infected diabetic large animal model available. Rodents, though used frequently, are not optimal for in vivo wound healing studies because of distinct differences with humans in terms of anatomy and wound-healing physiology (Wang et al., 2001). Also, while the acute response provides insight into the mechanisms that govern these fundamental processes, from a biological perspective, a chronic wound is not an acute wound that fails to heal even though it contains elements of the injury, inflammation, and repair. For normal acute healing, the management of the physical environment (e.g., control of bacterial contamination) might work very well but chronic wound conditions like a hard to heal diabetic foot ulcer can be biologically and physiologically far removed from the norm and might not show comparable results. All these uncertainties will have to be considered before planning an effective line of treatment. In conclusion, given that several factors influence the pathobiology of ulcers, it is extremely important that the podiatrist responsible for treating diabetic foot ulcers be fully aware of the biological processes of both normal and non-healing ulcers in order to be able to devise the best treatment protocols. References Axelrod, L 1985, ‘Infections in the diabetic patient’, Clinical Diabetes, vol.3, p.98. Al-Watban, FAH, Zhang, XY & Andres, BL 2007, ‘Low-Level Laser Therapy Enhances Wound Healing in Diabetic Rats: A Comparison of Different Lasers’, Photomedicine and Laser Surgery, vol. 25, no.2, pp. 72-77. doi:10.1089/pho.2006.1094. Bowering, CK 2001, ‘Diabetic foot ulcers. Pathophysiology, assessment, and therapy’, Canadian Family Physician, vol.47, 1007–1016 Viewed on 25 December 2008 http://www.pubmedcentral.nih.gov/ Bowler, PG, Duerden, BI & Armstrong, DG 2001, ‘Wound Microbiology and Associated Approaches to Wound Management’, Clinical Microbiology Reviews, vol.14, no.2, pp. 244–269. doi: 10.1128/CMR.14.2.244-269.2001. Boykin, JV Jr., Shawler, LG, Sommer, VL, Crossland, MC & Kalns, JE 1999, Diabetes-Impaired Wound Healing Predicted by Urinary Nitrate Assay - A Preliminary, Retrospective Study, Wounds vol.11, no.3, pp.62-69. Delamaire, M, Maugendre, D, Moreno, M, Le Goff, MC, Allannic, H & Genetet, B 1997, Impaired leucocyte functions in diabetic patients, Diabetes and Medicine, vol.14, no.1, pp.29-34 Enoch, S & Powell, P 2004, Cellular, molecular and biochemical differences in the pathophysiology of healing between acute wounds, chronic wounds and wounds in the aged. 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Grey, JE, Enoch, S & Harding, KG 2006, ‘Wound assessment’, BMJ vol. 332, pp. 285-288 doi:10.1136/bmj.332.7536.285, Viewed on 28 December 2008 http://www. bmj.com/ Huijberts, MSP, Schaper, NC & Schalkwijk, CG 2008, ‘Advanced glycation end products and diabetic foot disease’, Diabetes Metabolism Research Reviews, vol. 24(Suppl 1), S19–S24. King, L 2001, ‘Impaired wound healing in patients with diabetes’. Nursing Standard. vol. 15, no.38, pp. 39-45. Levine, JA 2002, ‘The development of a smart™ matrix to support robust fibroblast migration’, Viewed on 29 December 2008 http://www.sinc.sunysb.edu/Stu/jalevine/chronic%20ulcer%20theory.htm Mowat, A & Baum, J 1971, ‘Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus’, New England Journal of Medicine, vol. 284, pp.621-627. Pearl, S & Kanat, I 1988, ‘Diabetes and healing: a review of the literature’, Journal of Foot Surgery, vol. 27, pp. 268-273. 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