Arachidonic acid‐derived signaling lipids and functions in impaired healing

Abstract

Very little is known about lipid function during wound healing, and much less during impaired healing. Such understanding will help identify what roles lipid signaling plays in the development of impaired/chronic wounds. We took a lipidomics approach to study the alterations in lipid profile in the LIGHT−/− mouse model of impaired healing which has characteristics that resemble those of impaired/chronic wounds in humans, including high levels of oxidative stress, excess inflammation, increased extracellular matrix degradation and blood vessels with fibrin cuffs. The latter suggests excess coagulation and potentially increased platelet aggregation. We show here that in these impaired wounds there is an imbalance in the arachidonic acid (AA) derived eicosonoids that mediate or modulate inflammatory reactions and platelet aggregation. In the LIGHT−/− impaired wounds there is a significant increase in enzymatically derived breakdown products of AA. We found that early after injury there was a significant increase in the eicosanoids 11-, 12-, and 15-hydroxyeicosa-tetranoic acid, and the proinflammatory leukotrienes (LTD4 and LTE) and prostaglandins (PGE2 and PGF2α). Some of these eicosanoids also promote platelet aggregation. This led us to examine the levels of other eicosanoids known to be involved in the latter process. We found that thromboxane (TXA2/B2), and prostacyclins 6kPGF1α are elevated shortly after wounding and in some cases during healing. To determine whether they have an impact in platelet aggregation and hemostasis, we tested LIGHT−/− mouse wounds for these two parameters and found that, indeed, platelet aggregation and hemostasis are enhanced in these mice when compared with the control C57BL/6 mice. Understanding lipid signaling in impaired wounds can potentially lead to development of new therapeutics or in using existing nonsteroidal anti-inflammatory agents to help correct the course of healing.

Platelet Hyperactivity inTNFSF14/LIGHTKnockout Mouse Model of Impaired Healing

“…Moreover, we have recently shown that in these mice with impaired healing, platelets have enhanced aggregation as well as shorter bleeding time. 6 We also found that after injury there was a significant increase in the eicosanoids 11-, 12-and 15-HETE, and the proinflammatory leukotrienes (LTD 4 and LTE 4 ) and prostaglandins (PGE 2 and PGF 2a ) 6 that are important in platelet function.…”

“…[2][3][4] Prediction of healing outcomes remains elusive due to the lack of understanding of the mechanisms involved in the etiology of impaired and chronic wounds, and often the coexisting morbidities. Furthermore, although a murine model for chronic wounds has been developed recently, 5,6 mechanistic studies are still lacking, thereby hindering the advancement in the development of diagnostics and therapeutics to treat these wounds. [7][8][9] Tissue injury causes the disruption of blood vessels and extravasation of blood constituents.…”

Palmitoleic Acid has Stronger Anti‐Inflammatory Potential in Human Endothelial Cells Compared to Oleic and Palmitic Acids

“…Arachidonic acid is the most abundant polyunsaturated FA in most membrane phospholipids, and is typically linked with inflammation . Arachidonic acid can be mobilized by various phospholipase enzymes, most notably phospholipase A2, and subsequently be a substrate for synthesis of eicosanoids (prostaglandins, thromboxanes, and leukotrienes), by action of COX‐1 and COX‐2 and lipoxygenase enzymes .…”

Wound Healing and Omega-6 Fatty Acids: From Inflammation to Repair

“…Epoxyeicosatrienoic acids (EETs) are metabolites produced from AA due to cytochrome P450 (CYP450) activity, predominantly in the endothelium. EETs can stimulate angiogenesis and organ or tissue regeneration [ 21 , 99 ]. Local application of 11,12- or 14,15-EETs (10 μ M/methylcellulose discs) accelerated wound healing due to the increase in MMP2 and MMP7 and reduction in TIMP-1 and TNF- α during the proliferative phase of wound healing (12 days).…”