[Inhibitory effect of nafamostat mesilate (FUT-175) on O2- production in rat polymorphonuclear leucocytes]
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Abstract:
Effect of nafamostat mesilate (FUT-175), a serine protease inhibitor, having anti-inflammatory effects was studied on superoxide (O2-) production in rat polymorphonuclear leucocytes (PMN) and compared with those of other serine protease inhibitors and typical anti-inflammatory agents. 1) O2- productions in rat PMN stimulated with concanavalin A (Con A) and cytochalasin B (Cyt B) were too weak to observe. With NADH, however, strong O2- production was induced by Con A and Cyt B. 2) FUT-175 at 10(-6) and 10(-5) M inhibited O2- production in rat PMN induced by Con A and Cyt B with NADH in a concentration-dependent manner. 3) The serine protease inhibitor L-tosylamido-2-phenylethyl-chloromethyl ketone (TPCK) and soybean trypsin inhibitor (SBTI) inhibited O2- production at 10(-5) M and 10(-4) M, respectively, while aprotinin, chymostatin and leupeptin did not. 4) Neither indomethacin nor dexamethasone, typical anti-inflammatory agents, inhibited O2- production. Mepacrine, a phospholipase A2 inhibitor, strongly inhibited it. 5) O2- production in PMN prepared from the rat administered FUT-175, 200 mg/kg, p.o., was significantly decreased in comparison with that of the control rat. 6) FUT-175 had no effect on O2- production by hypoxanthine-xanthine oxidase. These results showed FUT-175 had a strong inhibitory effect on O2- production in rat PMN which other typical anti-inflammatory agents did not have.
Insights
Nafamostat mesilate (FUT-175), a serine protease inhibitor, effectively reduced superoxide production in rat immune cells. Unlike typical anti-inflammatory drugs, FUT-175 demonstrated significant inhibitory effects on this key inflammatory mediator.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Superoxide (O2-) production by polymorphonuclear leukocytes (PMN) is a critical component of the inflammatory response.
- Serine protease inhibitors are being investigated for their potential anti-inflammatory properties.
- Nafamostat mesilate (FUT-175) is a known serine protease inhibitor with reported anti-inflammatory effects.
Purpose of the Study:
- To investigate the effect of nafamostat mesilate (FUT-175) on superoxide (O2-) production in rat PMN.
- To compare the efficacy of FUT-175 with other serine protease inhibitors and conventional anti-inflammatory agents.
- To elucidate the mechanism underlying FUT-175's anti-inflammatory action.
Main Methods:
- Rat PMN were stimulated using concanavalin A (Con A) and cytochalasin B (Cyt B) in the presence of NADH to induce O2- production.
- The inhibitory effects of FUT-175, other serine protease inhibitors (TPCK, SBTI, aprotinin, chymostatin, leupeptin), and anti-inflammatory drugs (indomethacin, dexamethasone, mepacrine) on O2- production were assessed.
- In vivo studies involved oral administration of FUT-175 to rats, followed by assessment of O2- production in isolated PMN.
Main Results:
- FUT-175 significantly inhibited O2- production in rat PMN in a concentration-dependent manner.
- While TPCK and SBTI showed some inhibition, aprotinin, chymostatin, and leupeptin did not.
- Typical anti-inflammatory agents like indomethacin and dexamethasone were ineffective, whereas mepacrine (a phospholipase A2 inhibitor) showed strong inhibition. FUT-175 also demonstrated significant inhibition in vivo.
Conclusions:
- Nafamostat mesilate (FUT-175) possesses a potent inhibitory effect on superoxide production in rat PMN.
- This inhibitory effect is distinct from that of typical anti-inflammatory drugs, suggesting a unique mechanism of action.
- FUT-175's ability to suppress O2- production highlights its potential as a novel therapeutic agent for inflammatory conditions.