Contributors to wound chronicity:Investigating the role of age, peripheral nerves, and infection in the
development of non-healing cutaneous wounds
AbstractChronic wounds are a significant worldwide burden to patients and healthcare systems with millions of people suffering from them and treatments costing billions of dollars annually. A chronic wound is generally defined as a wound that is open for more than a month due to not progressing through the normal healing process. The wound healing process is complex involving many cell types and secreted signaling factors, all of which need to be tightly controlled both spatially and temporally. Therefore, it is important to fully understand the processes that govern physiological wound healing, to better recognize how it can become deranged and develop into a chronic wound. Additionally, chronic wounds are often complicated by the simultaneous presence of a combination of chronic diseases or co-morbidities. These include advanced age, infection, and metabolic conditions, but others are known. The most common metabolic disease associated with non-healing wounds is diabetes mellitus, which is associated with hyperglycemia, hyperlipidemia, peripheral neuropathy, and obesity that may also contribute. The work presented in this dissertation sought to better understand the contributions of two co-morbidities, advanced age and peripheral neuropathy, in the context of a third co-morbidity, infection, to the development of impaired wound healing.
There is an entrenched paradigm of delayed healing in aged individuals, however, some anomalous observations may challenge this paradigm. We investigated the fitness of the skin wound model in the aged mouse (22 months of age: human age-equivalent 65-70 years) compared to young mice (3 months: human age-equivalent 20 years) in both sexes and two strains and found no significant difference in healing. Therefore, we explored the parameters that may result in the contradictory interpretation of results in the literature. Additionally, analysis of serum catecholamine stress biomarkers in response to wound trauma revealed elevated dopamine and norepinephrine in the aged animals, suggesting an impaired outcome to wound infection, an additional stressor. When wounds were infected with Pseudomonas aeruginosa, the aged animals’ wounds had significantly reduced healing relative to similarly infected young animals. These findings suggest that there is a greater physiological stress associated with wound trauma in aged animals, which reduces their ability to heal when presented with a secondary challenge.
Skin sensory nerves play important roles in the homeostatic function of this barrier tissue, as well as in response to injury. Recent work has revealed the direct contribution of transient receptor potential cation channel, subfamily V member 1 (TRPV1) expressing sensory nerves in skin infection and disease. Thus, we hypothesized that TRPV1+ sensory nerves in the skin are involved in regulating the inflammatory phase of cutaneous wound healing, required for physiological progression of healing. Comparing wild type mice (C57BL/6) and mice lacking the TRPV1 channel (Trpv1-/-) revealed similar healing in uninfected excision wounds, though some cellular and molecular differences at baseline were observed. In view of these results, we pursued the role of TRPV1 in P. aeruginosa infected wounds and found delayed healing in the Trpv1-/- wounds and a number of immunophenotypic differences from C57BL/6, such as infiltrating immune cell frequency differences, elevated pro-inflammatory cytokine transcription, and defective dermal tissue repair on day 10. These results suggest that TRPV1 is associated with regulation of inflammation in response to wound infection. This study is a first step in understanding the role of nociceptors in cutaneous wound healing, but more work is needed to elucidate the direct contribution of TRPV1+ nociceptors. We believe this is a worthy investigation that may lead to improved therapies for infected diabetic foot ulcers.
