Lipoxin A(4) encapsulated in PLGA microparticles accelerates wound healing of skin ulcers

Lipoxin A(4) (LXA(4)) is involved in the resolution of inflammation and wound healing; however, it is extremely unstable. Thus, to preserve its biological activities and confer stability, we encapsulated LXA(4) in poly-lactic-co-glycolic acid (PLGA) microparticles (LXA(4)-MS) and assessed its application in treating dorsal rat skin lesions. Ulcers were sealed with fibrin adhesive and treated with either LXA(4)-MS, unloaded microparticles (Un-MS), soluble LXA(4), or PBS/glue (vehicle). All groups were compared at 0, 2, 7, and 14 days post-lesions. Our results revealed that LXA(4)-MS accelerated wound healing from day 7 and reduced initial ulcer diameters by 80%. Soluble LXA(4), Un-MS, or PBS closed wounds by 60%, 45%, and 39%, respectively. LXA(4)-MS reduced IL-1β and TNF-α, but increased TGF-β, collagen deposition, and the number of blood vessels. Compared to other treatments, LXA(4)-MS reduced inflammatory cell numbers, myeloperoxidase (MPO) concentration, and metalloproteinase-8 (MMP8) mRNA in scar tissue, indicating decreased neutrophil chemotaxis. In addition, LXA(4)-MS treatment increased macrophages and IL-4, suggesting a positive impact on wound healing. Finally, we demonstrated that WRW4, a selective LXA(4) receptor (ALX) antagonist, reversed healing by 50%, indicating that LXA(4) must interact with ALX to induce wound healing. Our results show that LXA(4)-MS could be used as a pharmaceutical formulation for the treatment of skin ulcers.