Aspirin Causes Delays in Wound Healing

Japanese researchers suggest that—in addition to promoting bleeding events—aspirin may also delay wound healing, in a new study published in The Journal of Experimental Medicine.

“We hope that the results from this study will evoke the cautions of many clinicians regarding the side effects of NSAIDs on wound healing,” says lead study author Takehiko Yokomizo, a professor in the Department of Biochemistry at Juntendo University School of Medicine in Tokyo. “At least, the use of high doses of aspirin should be avoided in patients with chronic wounds.”
_______________________________________________________________________________________________________________________________________________________________

RELATED CONTENT
Wound Infection: Primary Considerations
Chronic Wounds: A Continuing Challenge
_______________________________________________________________________________________________________________________________________________________________

The study sheds new light on how aspirin interacts with key skin cells called keratinocytes, which play an important role in restoring the epithelial layer over the wound surface. When these cells don’t migrate properly across a wound site, it is unable to heal adequately and develops into a chronic wound.

Yokomizo and colleagues investigated the role of 12-HHT, a molecule produced during blood coagulation following skin injury, and its receptor BLT2 in regulating keratinocyte migration to accelerate wound healing both in vivo and in vitro.

“The 12-HHT/BLT2 axis is critical in promoting epidermal keratinocyte migration, which is essential for re-epithelialization and restoration of an intact epidermal barrier after wounding,” Yokomizo says. The researchers discovered high doses of aspirin delay wound healing by reducing the production of 12-HHT.

They only employed a therapeutic high dose of aspirin in the study (0.18 mg/ml in drinking water). “As aspirin is quite a unique NSAID, high doses and low doses of aspirin exert different effects,” Yokomizo explains. “The conclusion from this study focuses on the notorious capacity of high doses of aspirin.”

The researchers also found that a synthetic form of BLT2 accelerated wound healing in diabetic mice. Their findings suggest BLT2 agonists could be used as therapeutic agents to accelerate wound healing, particularly for human intractable wounds, such as diabetic ulcers.

“Activation of BLT2 in the epidermal keratinocytes only accelerates cell migration, but surprisingly had no effect on keratinocyte proliferation, wound contraction, or skin inflammation,” Yokomizo says. “The findings indicate that BLT2 has its specific target cells in skin and a clear effect on keratinocytes, which make the BLT2 agonists promising therapeutic reagents with relatively fewer side effects.

He and his colleagues plan to further investigate the complex mechanisms of wound healing and develop drugs for the treatment of intractable wounds.

—Colleen Mullarkey

Reference

Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, et al. 12-hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor. J Exp Med. May 12, 2014. [Epub ahead of print]. doi:10.1084/jem.20132063.