ADVERSE EFFECTS OF TUMOUR NECROSIS FACTOR IN CYCLOPHOSPHAMIDE-TREATED MICE SUBJECTED TO GUT-DERIVEDPSEUDOMONAS AERUGINOSASEPSIS

Abstract

To evaluate the role of tumour necrosis factor (TNF) in gut-derived sepsis, mice were givenPseudomomas aeruginosastrain D4 by bacterial suspension in their drinking water during which time ampicillin (200 mg/kg) was given to disrupt the normal indigenous bacterial flora. Cyclophosphamide was additionally administered to induce bacterial translocation of theP. aeruginosathat had colonized the gastrointestinal tract, and thereby to cause gut-derived sepsis. In this model, TNF-α was detected in serum from the next day after the second cyclophosphamide administration, increasing to level of 3 ng/ml in lethal conditions. Average serum TNF-α level was significantly higher in mice with bacteraemia than in those without bacteraemia. Treatment with 0.8 μg/kg of recombinant human TNF-α (rhTNF-α) did not affect the mortality, whereas administration of either 4 and 20 μg/kg of rhTNF-α significantly increased the mortality rate in comparison with saline-treated mice. Bacterial counts in liver and blood were significantly higher in 20 μg/kg of rhTNF-α treated mice than in saline-treated mice. Treatment with murine anti-TNF-α monoclonal antibody significantly reduced the mortality from septic infection. We conclude that TNF-α may facilitate bacterial translocation and causes deterioration of gut-derived sepsis due toP. aeruginosain mice.