ScriptII. Summary of Wound Repair and AgingIt has been nearly a

ScriptII. Summary of Wound Repair and AgingIt has been nearly a century since it was noted that the rate of cutaneous scar formation after a wound is inversely related to the age of the Velpatasvir biological activity patient10. Four decades ago it was observed that older age was associated with an increased risk of postoperative disruption of the surgical wound, leading to higher mortality11. Recent data suggests that in patients older than 65 years, development of SSI is associated with a 2-fold rise in cost and a staggering 4fold increase in mortality12. Wound healing R848 site ensues via a sequential chain of events (with variable overlap) that includes inflammation, tissue formation and remodeling13 (Figure 2). Circulating factors have a pivotal role in each of these phases. Accordingly, immediate changes in the microcirculation influence each stage of the wound healing response in aging, as we will discuss below. Where human data is lacking, we will note data from established animal models of aging. Although not uniformly predictive of responses in human tissues14, several animal models of wound healing are generally accepted15. IIA. Inflammation Immediately following injury to the skin, local blood vessels constrict and circulating platelets attach to the endothelial wall to prevent further bleeding. The platelets aggregate and release their granules to form a fibrin clot. During this process, several mediators and cytokines that are also regulators of cell proliferation, extracellular matrix synthesis, and angiogenesis are released. As examples, transforming growth factor beta 1 (TGF-1) and platelet derived growth factor (PDGF) elicit rapid chemotaxis of neutrophils, monocytes and fibroblasts to the injured area, which stimulates generation of additional cytokines. The latter include the angiogenic factor vascular endothelial growth factor (VEGF), and the proinflammatory molecules tumor necrosis factor alpha and interleukin 1 beta16. Age-related changes in the inflammatory response (Figure 3A) result in alterations in cell adhesion, cell migration and cytokine production. In an aged mouse model of impaired wound healing, reduced phagocytosis by macrophages and delayed T cell infiltration into wounds were found in the aged mice relative to young mice. As expected, the production of most chemokines (measured by messenger RNA levels) declined with age by 20?0 17, but levels of some pro-inflammatory cytokines increase. Subsequent studies highlighted the critical role of macrophages: when young mice were injected at a biopsy wound site withAnesthesiology. Author manuscript; available in PMC 2015 March 01.Bentov and ReedPageanti-macrophage serum, they exhibited delayed closure of the wounds, similar to that of aged mice18. In contrast, aged mice wounds that were given peritoneal macrophages from young mice showed enhanced wound healing19. Interestingly, in old female mice, healing of full-thickness dermal wounds on the upper dorsum was accelerated by treadmill exercise, potentially reflecting an exercise-induced anti-inflammatory response in the wound20. Similarly, adult men (mean age 61 years) who exercised before an experimental wound showed a reduction in stress-related neuroendocrine responses that was accompanied by accelerated wound healing21. Another therapeutic intervention is suggested by the finding that castration of male mice is associated with a reduced inflammatory response and results in acceleration of cutaneous wound healing22. This might reflect suppression.ScriptII. Summary of Wound Repair and AgingIt has been nearly a century since it was noted that the rate of cutaneous scar formation after a wound is inversely related to the age of the patient10. Four decades ago it was observed that older age was associated with an increased risk of postoperative disruption of the surgical wound, leading to higher mortality11. Recent data suggests that in patients older than 65 years, development of SSI is associated with a 2-fold rise in cost and a staggering 4fold increase in mortality12. Wound healing ensues via a sequential chain of events (with variable overlap) that includes inflammation, tissue formation and remodeling13 (Figure 2). Circulating factors have a pivotal role in each of these phases. Accordingly, immediate changes in the microcirculation influence each stage of the wound healing response in aging, as we will discuss below. Where human data is lacking, we will note data from established animal models of aging. Although not uniformly predictive of responses in human tissues14, several animal models of wound healing are generally accepted15. IIA. Inflammation Immediately following injury to the skin, local blood vessels constrict and circulating platelets attach to the endothelial wall to prevent further bleeding. The platelets aggregate and release their granules to form a fibrin clot. During this process, several mediators and cytokines that are also regulators of cell proliferation, extracellular matrix synthesis, and angiogenesis are released. As examples, transforming growth factor beta 1 (TGF-1) and platelet derived growth factor (PDGF) elicit rapid chemotaxis of neutrophils, monocytes and fibroblasts to the injured area, which stimulates generation of additional cytokines. The latter include the angiogenic factor vascular endothelial growth factor (VEGF), and the proinflammatory molecules tumor necrosis factor alpha and interleukin 1 beta16. Age-related changes in the inflammatory response (Figure 3A) result in alterations in cell adhesion, cell migration and cytokine production. In an aged mouse model of impaired wound healing, reduced phagocytosis by macrophages and delayed T cell infiltration into wounds were found in the aged mice relative to young mice. As expected, the production of most chemokines (measured by messenger RNA levels) declined with age by 20?0 17, but levels of some pro-inflammatory cytokines increase. Subsequent studies highlighted the critical role of macrophages: when young mice were injected at a biopsy wound site withAnesthesiology. Author manuscript; available in PMC 2015 March 01.Bentov and ReedPageanti-macrophage serum, they exhibited delayed closure of the wounds, similar to that of aged mice18. In contrast, aged mice wounds that were given peritoneal macrophages from young mice showed enhanced wound healing19. Interestingly, in old female mice, healing of full-thickness dermal wounds on the upper dorsum was accelerated by treadmill exercise, potentially reflecting an exercise-induced anti-inflammatory response in the wound20. Similarly, adult men (mean age 61 years) who exercised before an experimental wound showed a reduction in stress-related neuroendocrine responses that was accompanied by accelerated wound healing21. Another therapeutic intervention is suggested by the finding that castration of male mice is associated with a reduced inflammatory response and results in acceleration of cutaneous wound healing22. This might reflect suppression.

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