2. Chronic Inflammation in Diabetic Wounds
The complete pathophysiology of ulceration is still unclear; however, clinicians and wound care specialists widely assert that delayed healing is due to complications of peripheral arterial diseases, neuropathy, inflammation, and ischemia . A combination of impaired growth factor production, angiogenic response, collagen accumulation, fibrosis, and abnormal pressure may result in ulceration and chronic cracks in the feet. Ultimately, the wound healing response at the ulceration site can be characterized by symptoms of a frustrated and prolonged inflammatory response.
Inflammation becomes activated within a day of ulcer formation and can last up to two weeks or longer. Inflammatory cells, such as neutrophils, macrophages, T-lymphocytes, fibroblasts, and prostaglandin E2 (PGE2) secrete enzymes that result in pain, redness, warmth, and swelling necessary for the healing cascade [10,11].
Neutrophils activate upon responding to chemotactic signals that allow for cell localization in the infected area. In a process called margination, neutrophils roll about the vasculature and migrate into the wound site with the help of cell adhesion molecules (CAMs) through diapedesis . The lack of functional adhesion molecules at this point in the inflammatory response delays healing . Neutrophils release elastase and collagenase for the purpose of destroying and removing damaged structural proteins. They also produce tumor necrosis factor alpha (TNF-α) and interleukins 1 (IL-1), to allow for fibroblast and epithelial cell homing .
Macrophages are the second key inflammatory cells needed for phagocytosis and releasing cytokines and growth factors, such as platelet derived growth factors (PDGF), transforming growth factors beta (TGF-β), beta fibroblast growth factors (β-FGF), TNF-α, IL-1, and IL-6 for promoting fibroblast proliferation and reepithelialization. Finally, lymphocytes, enter the wound and produce IL-2, needed to aid in fibroblast recruitment .
Read more Are Corn Flakes Good for Diabetes? Find Out Before Taking Another Spoonful
The role of fibroblasts in the healing process is significant because they produce matrix metalloproteinases (MMPs), which destroy impaired structural protein. They also release proteins that provide structural support for the new extracellular matrix . In chronic wounds, fibroblasts are non-receptive to cytokines and growth factors; as a result, their activity is impaired and there remains a distorted extracellular matrix . Fibroblasts release tissue inhibitor metalloproteinases (TIMPs) in order to regulate the effects of MMPs. Unregulated MMPs are overwhelming and destroy the old ECM in addition to fresh structural proteins .
Prostaglandin E2 (PGE2) is a hormone that is produced by blood vessels and promotes vasodilation and angiogenesis by inducing vascular endothelial growth factors (VEGFs). Thus, PGE2 is a vasodilator needed to prevent hypoxia. Individuals with DFUs suffer from vascular disease and peripheral arterial disease due to lower levels of PGE2 .
Primarily, ulcers occur through minor trauma in the presence of sensory neuropathy. Often, neuropathy is undiagnosed until ulcer formation or pain develops. Diabetes is associated with nerve damage, which results from diseased vasa nervorum and interacting metabolic abnormalities . Hyperglycemia may inhibit the production of nitric oxide, ultimately creating an environment that is more susceptible to reactive oxygen species, such as superoxide and hydrogen peroxide. This can disrupt the productivity of endothelium-derived vasodilator and can lead to a cascade of platelet aggregation, inflammation, thrombosis formation, and atherosclerosis of small vessels neighboring peripheral nerves, eventually leading to peripheral neuropathy. Although damage from neuropathy is irreversible, controlling blood glucose levels can prevent further ulceration. Other behavioral changes such as monitoring hyperglycemia, hypertension, smoking, cholesterol levels, and heavy alcohol use can prevent injury while promoting a better healing environment.
Read more Self-care Education Needs in Gestational Diabetes Tailored to the Iranian Culture: A Qualitative Content Analysis
Patients with diabetes may also have vascular disease and ischemia, which can contribute to delayed healing. In fact, ischemia is a major contributor in 90% of DFU patients who undergo amputation . Therefore, there is a high correlation between ischemia and atherosclerosis and highly infected DFUs. Capillary thickening can both interfere with normal flow of inflammatory cells and also create inelasticity, ultimately making it difficult for vasodilation needed for responding to local injury .
Because DFUs are chronic, treating infection can be challenging. Once an ulcer forms, infection can build and spread due to open air wounds, lack of sterility and a loss of innate barrier function . Dysfunctional leukocytes are common among the inflammatory response of patients with diabetes . Additionally, phagocytosis is reduced due to hyperglycemia, fibroblast migration is hindered, and the protective barrier and repair mechanism slows down. Normal wound exudate levels are optimized for healing, while in chronic wounds, exudate levels contain higher concentrations of MMP . MMP-2 and MMP-9 protein concentrations were 10 times and 25 times higher in pressure ulcer fluids than surgical fluids, respectively . The majority of pathogens found in DFUs are Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and anaerobic bacteria . Pathogen concentration levels above or equal to 105 Colony Forming Units (CFU) per gram are capable of interfering with the wound healing process . Bacteria proliferate toward this critical concentration level, and a biofilm forms as bacteria encase themselves within extracellular matrix substances of polysaccharides and lipids. Resistance to immunological responses becomes a significant problem for patients with infected chronic wounds.
Read more Can People with Diabetes Eat Brown Rice?