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A new way to accelerate wound healing

Wound healing is a dynamic process. First the body stimulates clotting factors to reduce blood loss. Then inflammation is initiated to protect wounded tissue from pathogens. After foreign agents are removed, tissue cells proliferate and new epithelial layers form. Many different molecules signal each other in every step of healing, which requires a balance between pro-inflammatory and anti-inflammatory processes. When the signaling cascades and inflammatory balance are impaired, a wound cannot heal.

Yaron Fuchs & Samara Brown/Rockefeller University

This confocal microscopy image from a mouse shows a tail wound in the process of healing.

Eicosanoids are signaling lipid molecules that play a role in mammalian wound response and impairment of that response; they include prostaglandins, thromboxanes and leukotrienes. An imbalance between anti-inflammatory eicosanoids, such as prostaglandins, and proinflammatory eicosanoids, such as epoxyeicosatrienoic acids, causes wound healing problems. Thus, researchers study different ways of regulating eicosanoid expression to develop more efficient healing.

Eicosanoids are synthesized by activity of phospholipase A2, or PLA2, which is activated by ceramide-1-phosphate, or C1P — a key regulator of cell growth and survival that plays a crucial role in cell division and DNA synthesis. C1P is regulated by ceramide kinase, or CERK, enzymes, and previous studies have shown that downregulation of CERK blocks PLA2 activation, which causes eicosanoids to be depleted in response to inflammation.

Kenneth D. Maus at the University of South Florida, Tampa, and a team of researchers from the University of Virginia School of Medicine and elsewhere in the U.S. targeted the CERK enzyme by generating small-molecule inhibitors and by genetic manipulation to observe its effect on wound healing. Their about this work was published recently in the Journal of Lipid Research.

The group developed a small-molecule inhibitor against CERK, and they genetically modified mice to have ablated CERK synthesis. They showed that CERK inhibition or ablation accelerates the transition from inflammation to proliferation in wounds. These results suggest that inhibition of CERK enhances wound healing and maturation of the tissue, and they provide preclinical data to explore future human clinical application.