Download A novel mechanism of aspirin action on skin wound healing

A novel mechanism of aspirin action on skin wound healing
Takehiko Yokomizo
Department of Biochemistry, Juntendo University School of Medicine, Tokyo. Japan
Aspirin, the most famous non steroidal anti-inflammatory drug (NSAID), is widely used to kill pain
and fever by inhibiting cyclooxygenases to produce prostaglandins (PGs). Aspirin is also famous
for its serious side effects including mucosal damage of gastrointestinal tracts and delay in skin
wound healing. Although reduced production of prostaglandins by aspirin is generally accepted as a
common mechanism for these side effects, several reports using genetically engineered mice that
lack PG production and PG receptors failed to prove the mechanism. We found that
aspirin-dependent reduction of 12-hydroxyheptadecatrienoic acid (12-HHT), an endogenous ligand
for leukotriene B4 receptor type 2 (BLT2), is responsible for the delay in skin wound healing.
Aspirin delayed the wound closure after skin punching in mice, which was completely abolished in
BLT2-deficient mice. Furthermore, mice deficient in BLT2 or thromboxane A2 synthase, a
responsible enzyme for 12-HHT production, exhibited delayed wound healing. 12-HHT is produced
during blood coagulation and activates BLT2 expressed in keratinocytes to release tumor necrosis
accelerated wound closure in vitro and in C57BL/6J and db/db mice. Our results clarify the novel
mechanism of aspirin actions, and BLT2 agonists are possible therapeutic drugs for wounds
especially for diabetic ulcer.
References
1.
Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., Shimizu, T. A G-protein-coupled receptor for leukotriene B4 that
mediates chemotaxis. Nature 387(6633): 620-624 (1997)
2.
Yokomizo, T., Kato, K., Terawaki, K., Izumi, T., Shimizu, T. A second leukotriene B(4) receptor, BLT2. A new
therapeutic target in inflammation and immunological disorders. J Exp Med 192(3): 421-432 (2000)
3.
Okuno, T., Iizuka, Y., Okazaki, H., Yokomizo, T., Taguchi, R., Shimizu, T. 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic
acid is a natural ligand for leukotriene B4 receptor 2. J Exp Med 205(4): 759-766 (2008)
4.
Matsunobu, T., Okuno, T., Yokoyama, C., Yokomizo, T. Thromboxane A synthase-independent production of
12-hydroxyheptadecatrienoic acid, a BLT2 ligand. J Lipid Res 54(11): 2979-2987 (2013)
5.
Liu, M., Saeki, K., Matsunobu, T., Okuno, T., Koga, T., Sugimoto, Y., Yokoyama, C., Nakamizo, S., Kabashima, K.,
Narumiya, S., Shimizu, T., Yokomizo, T. 12-hydroxyheptadecatrienoic acid promotes epidermal wound healing by
accelerating keratinocyte migration via the BLT2 receptor. J Exp Med 211(6): 1063-1078 (2014)