However, in rats, TNF-a blockade appears to blunt hemodynamic disturbances in a model of portal hypertension, and reduce episodes of BT in a model of cirrhosis. These data suggest that modulation of the inflammatory response might improve survival, supporting our hypothesis that the use of a selective mAb against TNF-a together with ceftriaxone would decrease mortality in an intraperitoneal infection episode. Since TNF-a is part of the normal immune response against bacterial infections, it is necessary to investigate whether the administration of anti-TNF-a mAb might result in an increased risk of bacterial superinfections. However, in the present study we did not observe superinfections in surviving rats treated with antibiotics and anti-TNF-a mAb. There were two main analytical findings when comparing samples obtained immediately after i.p. administration of E. coli and at laparotomy in surviving rats: first, baseline NOx was the only parameter to show statistically significant differences between surviving and dying rats. This information is similar to that reported in patients with SBP, and may be related to repeated episodes of BT and stimulation of the immune response prior to i.p. injection with E. coli. Indeed, bacteria components such as lipopolysacharide or DNA stimulate the immune response through joining toll-like receptors 4 and 9, respectively,, and it is likely that higher NOx levels will correlate with more severe haemodynamic disturbances in this model. Second, TNF-a levels decreased significantly in surviving animals when receiving ceftriaxone alone or in combination with mAb, although values only reached significance in the combination therapy arm. This seems logical when considering the specificity of anti-TNF-a mAb used in this investigation. No differences in the rate of BT were observed when comparing animals included in Groups II or III. These results are similar to others previously reported by our group that showed that anti-TNF-a mAb in non-infected rats with cirrhosis does not increase the likelihood of developing infections. In this investigation, however, rats were infected, and the trend towards an increased persistence of bacteria in mesenteric lymph nodes in animals receiving the combination therapy may point to a decreased ability to fight against infection once it is established. Caution should therefore be recommended when considering the immune modulation with administration of anti-TNF-a mAb in an active infection setting. TNF-a blockade may be also achieved by several nonmonoclonal related molecules. Xanthine derivatives such as pentoxifylline or serotonin 5-hydroxytryptamine receptor agonists such as 2,5-dimethoxy-4-iodoamphetamine are potent TNF-a inhibitors that might be use to confirm presented data. In addition, the use of these molecules would avoid the formation of anti-drug antibodies. In conclusion, the administration of ceftriaxone and anti-TNF-a mAb decreases serum TNF-a levels. However, in the present study we did not observe significant differences on survival in cirrhotic rats with induced bacterial peritonitis treated with antibiotics with or without anti-TNF-a mAb. Additional studies including more animals are required to assess if the association of antibiotic therapy and TNF-a blockade might be a possible approach to reduce mortality in cirrhotic patients with bacterial peritonitis, before this therapeutic combination can be recommended.
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