Lipoxin A4 encapsulated in PLGA microparticles accelerates wound healing of skin ulcers

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.

Lipoxin suppresses inflammation via the TLR4/MyD88/NF‐κB pathway in periodontal ligament cells

“…In addition, the results showed that a fewer amount of TNFα was secreted in cells treated with LXA4. These results are consistent with previous studies, where treatment with LXA4 resulted in a decrease in pro-inflammatory cytokines (Gaudin et al, 2018;Pouliot et al, 2000;Reis et al, 2017).…”

Eicosanoids in tissue repair

“…While the role of 12‐ and 15‐HETE in tissue repair is largely unclear, LXA 4 has been implicated in tissue regeneration as it could reduce inflammation and promote re‐epithelialization in the eye . Moreover, the administration of LXA 4 ‐containing microparticles in a rat model of skin wound healing promoted wound closure, angiogenesis and collagen deposition, potentially by inducing IL‐4, TGFβ1 and tissue repair macrophages . Intriguingly, 12‐/15‐LOX is generally highly expressed during type 2 immune responses, for example after exposure to house dust mite or during intestinal nematode infection .…”

“…8 Moreover, the administration of LXA 4 -containing microparticles in a rat model of skin wound healing promoted wound closure, angiogenesis and collagen deposition, potentially by inducing IL-4, TGFb1 and tissue repair macrophages. 59 Intriguingly, 12-/15-LOX is generally highly expressed during type 2 immune responses, for example after exposure to house dust mite or during intestinal nematode infection. 15,60 This may suggest that 12/ 15-LOX also plays important roles in epithelial barrier repair in mucosal tissues such as the airways and intestine.…”

Inhibition of Osteoclast Differentiation and Activation by Leukotriene B4 Loaded in Microspheres

“…The microspheres were prepared using a polymer, the co-glycolic poly-lactic acid (PLGA) as a scaffold. PLGA is widely used for preparation of microspheres because it is a biodegradable and biocompatible polymer (Fredenberg et al, 2011;Pereira et al, 2015;Reis et al, 2017;Lorencetti-Silva et al, 2019). This material allows the release of encapsulated molecules in a controlled manner for long periods and from a single administration, which keeps the concentrations of the encapsulated substance constant (Ford Versypt et al, 2012).…”

“…Therefore, the aim of this study was to investigate the role of leukotriene B4 in the differentiation of cells from the monocytic lineage (J774A.1) into osteoclasts, after stimulation with leukotriene B4 encapsulated in microspheres. This therapeutic strategy, based on the use of polylactic-co-glycolic acid microspheres (PLGA), promote a sustained delivery of lipid mediator over time since lipid mediators are extremely labile (Nicolete et al, 2009;Santos et al, 2011;Pereira et al, 2015;Reis et al, 2017;Lorencetti-Silva et al, 2019).…”