Suppression of the acute inflammatory response of porcine alveolar‐ and liver macrophages

Abstract

During infection and inflammation drug disposition and hepatic metabolism are markedly affected in mammals. Pro‐inflammatory mediators play an important role in the suppression of (cytochrome‐P450‐mediated) drug metabolism. Inflammatory mediators like cytokines, nitric oxide (NO), reactive oxygen species (ROS) and eicosanoids are released by activated macrophages from various sources, including liver and lung.

It was the aim of this study to investigate ways to suppress the activation of macrophages during the onset of the inflammatory cascade. Therefore porcine lung and liver macrophages were isolated, and incubated with lipopolysaccharide (LPS) to initiate an acute inflammatory response, represented by the release of high amounts of tumour necrosis factor‐α (TNF‐α) into the culture medium. Additionally the primary macrophages were coincubated with phosphodiesterase‐IV‐ (PDE‐IV)‐inhibitors or ß‐adrenoceptor agonists that in previous studies demonstrated strong suppressive effects on TNF‐α release. Especially the ß‐adrenoceptor agonists showed to be very potent TNF‐α suppressants, which indicates that the ß‐adrenoceptor might be an interesting target for suppression of activation of macrophages. This was strengthened by the observation that the ß‐adrenoceptor expression was not altered during the onset of the inflammatory cascade.

Key words:

• macrophages
• porcine
• inflammation
• LPS
• TNF‐α

Notes

Department of Pharmacology, TNO Pharma, P.O. Box 360, 3700 AJ Zeist, the Netherlands.

Department of Veterinary Pharmacology Pharmacy, and Toxicology, Utrecht University, P.O. Box 80152, 3508 TD Utrecht, the Netherlands.

Drug Metabolism Research, Pharmacia & Upjohn, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Corresponding author: CA. Izeboud, TNO‐Pharma, P.O. Box 360, 3700 AJ, Zeist, The Netherlands. Telephone: + 31 30 6944958, fax: + 31 30 6956742, email: [email protected]

Additional information

Notes on contributors

C.A. Izeboud

1 *

R.F. Witkamp

1 2