Aspirin topic treatment improves cutaneous wound healing in diabetic mice through lipoxygenase‐dependent production of pro‐resolving lipid mediator
Résumé
Introduction: Healing disorders are one of the leading causes of morbidity and mortality of diabetic patients. The understanding of the deregulation of cellular and molecular mechanisms of the wound healing process is a key issue for the development of new therapeutic strategies. Delayed healing in diabetic patients is due to dysregulations of the inflammatory process. The arrest of inflammatory phase, which involves the recruitment of polarized M2 macrophages, is a key step in the resolution of inflammation and tissue repair. Our hypothesis was that deregulation of diabetic wound healing was the result of an impairment in the polarization of macrophages.
Methods: We developed a new full‐thickness wound model in type 2 diabetic mice (in high fat diet or db/db mice) associated with the development of an innovative device to treat the wound, follow its evolution and characterized phenotypically and functionally cells within the exsudates.
Results: We demonstrated that the severe impairment of healing in diabetic mice is correlated to a strong neutrophil and inflammatory macrophage M1 infiltration, a lack of influx of anti‐inflammatory macrophages M2, leading to a failure in the inflammatory cells apoptosis and efferocytosis. We established a decrease of lipoxin A4 (LXA4), a bioactive lipid from arachidonic acid (AA) metabolism involved in the resolution of inflammation, and an increase of potent chemotactic lipid leukotriene B4 (LTB4). We demonstrated that topical daily application of acetylsalicylic acid on the wound, 3 days after the skin lesion, orients the AA metabolism towards the synthesis of LXA4 at the expense of LTB4, triggers the recruitment of M2‐polarized macrophages, and promotes apoptosis of neutrophils and their efferocytosis.
Conclusions: The resolution of inflammation by an original mechanism toward the 12/15‐LOX induction regardless of the COX‐2 expression allows us to envisage the development of a new therapeutic strategy to promote diabetic wound healing.