Promoting improved healing: Lessons learned from the fetus

ABSTRACT

Background: It has long been known that the fetal response to skin injury is regenerative, with a lack of abnormal collagen deposition or scar, and restoration of normal dermal architecture. This response is associated with minimal inflammation.We have shown that the decreased inflammation is due to decreased production of pro-inflammatory cytokine production compared to the adult response. In addition, we have shown fetal tendon and the fetal heart can heal by regeneration, with restoration of structure and function, and is also associated with decreased proinflammatory cytokine production and decreased inflammation. We hypothesized that strategies targeting inflammation and associated oxidative stress could be used in adult diseases. We have identified diabetic wounds, acute lung injury, and colitis where inflammation and oxidative stress plays a central role in the pathogenesis the disease. Material(s) and Method(s) We have developed a novel strategy using nanotechnology to target inflammation and oxidative stress. We have conjugated novel cerium oxide nanoparticles, which act as potent scavengers of reactive oxygen species, to the anti-inflammatory microRNA miR146a, which suppresses the NFkB pathway and the production of the pro-inflammatory cytokines IL-6 and IL-8. Result(s) In diabetic wounds, impaired healing is associated with chronic inflammation and oxidative stress. We have demonstrated, in both small and large diabetic animals models, that CNP-miR146a can decrease inflammation and oxidative stress and correct the diabetic wound healing impairment and promote regeneration, similar to rates of healing in non-diabetic animals. We have also examined other disease states where inflammation and oxidative stress is pathogenic. Following acute lung injury, inflammation and oxidative stress leads to the development of adult respiratory distress syndrome or ARDS, the number one cause of mortality with COVID-19, and is associated with a 30-50% mortality. Inflammation and oxidative stress play a central role in the pathogenesis of ARDS. We have shown in models of acute lung injury, including bleomycin, LPS, MRSA, ventilator induced lung injury (VILI) and mustard gas, that CNP-miR146a decreases inflammation and oxidative stress, promotes regeneration and restoration of function, and decreased mortality. Finally, pathogenic inflammation plays a central role in the development of colitis or inflammatory bowel disease. We have shown that CNP-miR146a enemas can prevent progression of disease, restore weight gain, and lacks the adverse effects of systemic immunosuppression. Conclusion(s) We have used our understanding of the mechanisms of fetal regeneration following injury, which progresses with minimal inflammation and oxidative stress, to develop strategies targeting these processes to promote regeneration in adult disease.