Effects of 2-benzoylamino-benzoic acid analogues on superoxide anion and elastase release in human neutrophils

• Main Authors: Yi-Ju Chang, 張一如
• Other Authors: Tsong-Long Hwang
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/28719490541449645279

碩士 === 長庚大學 === 天然藥物研究所 === 95 === Reactive oxygen species and granule proteases produced by neutrophils contribute to the pathogenesis of inflammatory diseases, such as rheumatoid arthritis, myocardial infarction, chronic obstructive pulmonary disease, and asthma. Suppression of the extensive or inappropriate activation of neutrophils has been proposed to ameliorate these inflammatory diseases. There are, in spite of this, only a few currently available agents that directly modulate neutrophil pro-inflammatory responses in clinical practice. In a search for new anti-inflammatory agents, the effects of 2-benzoylamino-benzoic acid analogues on superoxide anion (O2.-) and elastase release in human neutrophils was tested. Among them, DSM-RX 78 and DSM-RX 116 showed the most-potent and specific inhibition on O2.- production in formyl-methionyl-leucyl-phenylalanine-activated (FMLP)-activated human neutrophils. In addition, DSM-RX 100-105 had the most-potent and specific inhibition on elastase release in FMLP-induced human neutrophils. These inhibitory effects were not due to cytoxicity because culturing with these compounds did not cause lactate dehydrogenase release. DSM-RX 78 and DSM-RX 116 displayed no antioxidant or O2.--scavenging ability, and they failed to alter the subcellular NADPH oxidase activity. DSM-RX 78 and DSM-RX 116 did not affect PKC activator-induced O2.- generation in neutrophils. Specially, inhibitory effects of DSM-RX 78 and DSM-RX 116 on O2.- production were completely reversed by PKA inhibitors. DSM-RX 78 and DSM-RX 116 increased the FMLP and PGE1, but not the rolipram, induced cAMP formation, suggesting inhibition of phosphodiesterase (PDE). Consistent with this, DSM-RX 78 and DSM-RX 116 potentiated the PGE1-caused inhibition of elastase release, which were almost abolished by the PKA inhibitor. On the other hand, DSM-RX 100-105 had a direct inhibitory effects on enzymatic activity of human neutrophil elastase in cell-free systems. In summary, these results demonstrate that inhibition of inflammatory responses in human neutrophils by DSM-RX 78 and DSM-RX 116 are associated with an elevation of cellular cAMP through inhibition of PDE. In addition, our data also indicate that DSM-RX 100, DSM-RX 101, DSM-RX 102, DSM-RX 103, DSM-RX 104, and DSM-RX 105 are elastase inhibitors. These results will provide new insight into the mechanisms of 2-benzoylamino-benzoic acid analogues, supporting the hypothesis that 2-benzoylamino-benzoic acid analogues may have the potential to protect against the progression of inflammatiory diseases.