Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce inflammation by suppressing cyclooxygenases (COXs). NSAID eye drops are frequently prescribed after ocular surgery to reduce inflammation and pain, but this treatment has clinically significant side effects, including corneal ulcer and perforation. The molecular mechanisms underlying these side effects remain unknown. Recently, the COX product 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) was identified as an endogenous ligand for leukotriene B4 receptor 2 (BLT2), which is important in maintenance of epithelial homeostasis. We hypothesized that NSAID-dependent corneal damage is caused by reduced production of 12-HHT. Diclofenac eye drops decreased the abundance of downstream products of COX and delayed corneal wound healing in BALB/c mice. Expression of BLT2 was observed in murine ocular tissues including cornea, and in human corneal epithelial cell line and human primary corneal epithelial cells. In BLT2-knockout mice, corneal wound healing was delayed, but the diclofenac-dependent delay in corneal wound healing disappeared. 12-HHT accelerated wound closure both in BLT2-transfected corneal cell line and human primary corneal epithelial cells. Thus, our results reveal that NSAIDs delay corneal wound healing by inhibiting 12-HHT production, and suggest that stimulation of the 12-HHT/BLT2 axis represents a novel therapeutic approach to corneal wound healing.
Highlights
Leukotriene B4 receptor 2 (BLT2), a class A G-protein–coupled receptor (GPCR), was originally identified in our laboratory as a low-affinity receptor for leukotriene B4 (LTB4)[1]
We generated a murine model of corneal wound healing and used it to examine the effects of Non-steroidal anti-inflammatory drugs (NSAIDs)
To test the effects of NSAIDs in this system, the mice were treated with eye drops containing 0.1% diclofenac, almost the same concentration used in human patients in clinical settings, four times a day for 2 days
Summary
Leukotriene B4 receptor 2 (BLT2), a class A G-protein–coupled receptor (GPCR), was originally identified in our laboratory as a low-affinity receptor for leukotriene B4 (LTB4)[1]. Based on the observation of BLT2 expression in murine and human corneal epithelium, we hypothesized that delayed corneal wound healing by NSAIDs might be due to reduced production of 12-HHT and subsequent inhibition of BLT2 signaling. These data suggest that NSAIDs delay corneal wound healing in mice, possibly due to the reduced production of eicosanoids in ocular surface tissues of the eye. BLT2 is expressed in corneal epithelial cells in mouse and human.
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