The effect of nonsteroidal anti-inflammatory agents on E. coli-induced inflammation.

Indomethacin and acetylsalicylic acid (ASA) have recognized anti-inflammatory activity. Here we report the effect of these nonsteroidal anti-inflammatory drugs on the kinetics of the inflammatory reaction induced by the intradermal injection into rabbits of killed E. coli. Simultaneous quantitation of blood flow, using 86Ru, vascular permeability, using 125I-albumin, and leukocyte infiltration, using 51Cr-labeled leukocytes was performed. Treatment of rabbits systemically with indomethacin (100 mg/m2; 6 mg/kg ip) inhibited the blood flow, vascular permeability, and leukocyte infiltration, although the inhibition of the latter did not reach statistical significance. Indomethacin and ASA were also administered locally intradermally (id) into skin sites together with the E. coli in the same rabbit in order to minimize animal to animal variations in leukocyte infiltration. Both drugs again inhibited the blood blow and vascular permeability in the lesions. Furthermore, they significantly inhibited leukocyte infiltration. All of these effects were completely reversed by the id injection of prostaglandin E2 in a dose (0.5 microgram) that, in normal skin, increased only the blood flow. These observations indicate that indomethacin and ASA act primarily by decreasing vascular responses during inflammation, probably by inhibiting prostaglandin synthesis at the site. The suppression of leukocyte infiltration appears to be a secondary effect due to the inhibition of the hyperemia and hyperpermeability during inflammation. These findings emphasize the important role played by the vascular responses in regulating the rate of leukocyte infiltration.