Abstract
Lipoxin A4 (LXA4) 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 LXA4 in poly-lactic-co-glycolic acid (PLGA) microparticles (LXA4-MS) and assessed its application in treating dorsal rat skin lesions. Ulcers were sealed with fibrin adhesive and treated with either LXA4-MS, unloaded microparticles (Un-MS), soluble LXA4, or PBS/glue (vehicle). All groups were compared at 0, 2, 7, and 14 days post-lesions. Our results revealed that LXA4-MS accelerated wound healing from day 7 and reduced initial ulcer diameters by 80%. Soluble LXA4, Un-MS, or PBS closed wounds by 60%, 45%, and 39%, respectively. LXA4-MS reduced IL-1β and TNF-α, but increased TGF-β, collagen deposition, and the number of blood vessels. Compared to other treatments, LXA4-MS reduced inflammatory cell numbers, myeloperoxidase (MPO) concentration, and metalloproteinase-8 (MMP8) mRNA in scar tissue, indicating decreased neutrophil chemotaxis. In addition, LXA4-MS treatment increased macrophages and IL-4, suggesting a positive impact on wound healing. Finally, we demonstrated that WRW4, a selective LXA4 receptor (ALX) antagonist, reversed healing by 50%, indicating that LXA4 must interact with ALX to induce wound healing. Our results show that LXA4-MS could be used as a pharmaceutical formulation for the treatment of skin ulcers.
Highlights
Wound healing is a complex process in which tissues are repaired post injury
We demonstrated that Lipoxin A4 (LXA4)-MS applied to rat skin ulcers were more effective than soluble LXA4 in accelerating the wound healing process
We found 800-ng/10 mg or an encapsulation efficiency of 32%. This finding was lower than we observed for leukotriene B4 (LTB4) or prostaglandin E2 (PGE2), which had encapsulation efficiencies of 50% and 75%, respectively [18,19,22]
Summary
Wound healing is a complex process in which tissues are repaired post injury. Wound healing is divided into inflammatory, proliferative, and remodeling phases [1] that result in scar formation. Scarring involves recruitment of cells, growth factors, cytokines, and eicosanoids along with the release of enzymes to elicit extracellular matrix formation [1,2]. Pathological alterations of each phase are related to wound exacerbation or an inefficient healing process. Lipoxin A4 in PLGA-MS improves wound healing
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