Phosphodiesterase inhibition downregulates intestinal injury and inducible nitric oxide synthase activity after hemorrhagic shock

Objective. Previous work suggests that supplementation of Ringer's lactate (RL) resuscitation with pentoxifylline (PTX) abrogates distant organ injury after hemorrhage. The aim of this work was to determine whether PTX can effectively attenuate resuscitation-induced intestinal injury and pro-inflammatory mediator production. Material and methods. Male Sprague-Dawley rats underwent 60 min of hypotension followed by resuscitation with RL or RL + PTX (25 mg/kg). The ileum was examined for injury. Nitric acid and pro-inflammatory cytokines were measured using an enzyme-linked immunosorbent assay. Inducible nitric oxide synthase (iNOS) and phosphorylation of nuclear factor (NF)-κB and signal transducer and activator of transcription (STAT)-3 were evaluated using Western blotting. Results. RL resuscitation led to a marked increase in all parameters over the control. The addition of PTX significantly reduced histologic injury and levels of iNOS, NO, tumor necrosis factor-α, interleukin-6, and cytokine-induced neutrophil chemoattractant (p<0.05). RL-induced phosphorylation of cytoplasmic IκB-α, nuclear NF-κB, and STAT3 was abrogated with PTX supplementation. Conclusion. Intestinal injury and activation of iNOS-mediated pathways associated with RL resuscitation were significantly reduced when PTX was used as an adjunct to standard RL treatment.