Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes.

Dysfunction of macrophages (MΦs) in diabetic wounds impairs the healing. MΦs produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by MΦs and the actions of NPD1 on diabetic MΦ functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, MΦ depletion, MΦs isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of MΦs in NPD1 biosynthesis, and NPD1 action on diabetic MΦ inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated MΦs from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by MΦs. NPD1 enhanced wound healing and innervation in diabetic mice and promoted MΦs functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated MΦs involved 1) attenuating MΦ inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing MΦ production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a MΦs-produced factor that accelerates diabetic wound healing and promotes MΦ pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic MΦs for treatment of diabetic wounds.

Maresin-like lipid mediators are produced by leukocytes and platelets and rescue reparative function of diabetes-impaired macrophages.

Nonhealing diabetic wounds are associated with impaired macrophage (Mf) function. Leukocytes and platelets (PLT) play crucial roles in wound healing by poorly understood mechanisms. Here we report the identification and characterization of the maresin-like(L) mediators 14,22-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acids, 14S,22-diHDHA (maresin-L1), and 14R,22-diHDHA (maresin-L2) that are produced by leukocytes and PLT and involved in wound healing. We show that 12-lipoxygenase-initiated 14S-hydroxylation or cytochrome P450 catalyzed 14R-hydroxylation and P450-initiated ω(22)-hydroxylation are required for maresin-L biosynthesis. Maresin-L treatment restores reparative functions of diabetic Mfs, suggesting that maresin-Ls act as autocrine/paracrine factors responsible for, at least in part, the reparative functions of leukocytes and PLT in wounds. Additionally, maresin-L ameliorates Mf inflammatory activation and has the potential to suppress the chronic inflammation in diabetic wounds caused by activation of Mfs. These findings provide initial insights into maresin-L biosynthesis and mechanism of action and potentially offer a therapeutic option for better treatment of diabetic wounds.

Neuropathic plantar forefoot ulcers treated with tendon lengthenings.

BACKGROUND: Foot ulcers are a common cause of infection and amputation in patients with neuropathy. This retrospective study evaluated the healing and recurrence rates after treating neuropathic ulcers plantar to the metatarsal heads with tendon lengthenings in the leg. MATERIALS AND METHODS: Between 1995 and 2003, 20 ulcers plantar to the metatarsal heads in 17 patients were treated with tendon lengthenings. All patients had gastroc-soleus recession (Vulpius procedure). Patients with first metatarsal head ulcers also had Z-type lengthenings of the peroneus longus. Patients with fifth metatarsal head ulcers also had intramuscular lengthening of the tibialis posterior. Patients with second, third, and fourth metatarsal head ulcers had only a gastroc-soleus recession. RESULTS: All patients had neuropathy; 15 patients with 17 ulcers had diabetes mellitus. All incisions healed primarily without infection. Nineteen of 20 ulcers healed. One patient with one ulcer was lost to followup after the ulcer healed. Average followup for the remaining 19 ulcers was 45 months. Average duration of the 19 ulcers before surgery was 17 months. Three of 19 ulcers recurred and had repeat tendon lengthening and healed again. None of the patients whose ulcers healed had to be admitted for foot infection or amputation. The one patient whose ulcer did not heal developed progressive dry gangrene which required trans-femoral amputation six months after tendon lengthening. CONCLUSION: Tendon lengthenings in the leg seem to be effective in healing and preventing recurrence of neuropathic ulcers plantar to the metatarsal head with a low complication rate.