THE SPECIFIC TYPE-IV PHOSPHODIESTERASE INHIBITOR ROLIPRAM COMBINED WITH ADENOSINE REDUCES TUMOR NECROSIS FACTOR-ALPHA-PRIMED NEUTROPHIL OXIDATIVE ACTIVITY

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alp ha) in response to microbial products including endotoxin. TNF alpha i s a potent primer of neutrophil (PMN) oxidative activity. Certain xant hine phosphodiesterase (PDE) inhibitors such as pentoxifylline have be en shown to inhibit stimulated oxidative activity in PMN. In the prese nt study, the non-xanthine PDE type IV inhibitor rolipram [3'-cyclopen tyloxy-4'methoxyphenyl]-2-pyrrolidone) alone and in combination with a denosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergist ically decreased rhTNF alpha-primed suspended PMN oxidative activity s timulated by the chemoattractant f-met-leu-phe. The rolipram effect wa s reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especia lly when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A(2a) rece ptor agonists CGS 21680 and WRC-0474 had comparable activity to adenos ine in these experiments. Adenosine (or CGS 21680) combined with rolip ram synergistically increased f-met-leu-phe-stimulated PMN cAMP conten t. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kina se A inhibitor KT 5720, indicating that protein phosphorylation is onl y partially involved. Rolipram activity was about 1000x (by molar conc entration) greater than pentoxifylline in comparable assays. Thus, rol ipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.