Combination therapy that targets secondary pulmonary changes after abdominal trauma

After abdominal trauma, the lung is susceptible to secondary injury caused by acute neutrophil (PMN) sequestration and alveolar capillary membrane dis ruption. Adenosine is an endogenous anti-inflammatory metabolite that decre ases PMN activation. AICAR ([5-amino-1-{beta -D-ribofuranosyl}imidazole-4-c arboxamide]riboside) is the prototype of a novel class of anti-inflammatory drugs that increase endogenous adenosine. After trauma, AICAR administrati on has been shown to decrease secondary lung injury in models of hemorrhagi c shock with delayed lipopolysaccharide challenge and pulmonary contusion. However, early suppression of PMN activation could worsen outcomes after pe netrating abdominal trauma. We hypothesized that, after penetrating abdomin al trauma, the ideal resuscitation strategy would involve early, short-live d suppression of PMN activation to minimize secondary lung injury, followed by later enhancement of PMN chemotaxis and phagocytosis [using granulocyte colony-stimulating factor (G-CSF)] to lessen late septic complications. G- CSF has not been shown to potentiate PMN mediated pulmonary reperfusion inj ury. Swine were subjected to cecal ligation/incision and hemorrhagic shock (trauma), followed by resuscitation with shed blood, crystalloid, and eithe r G-CSF, a combination of G-CSF and AICAR, or 0.9% normal saline. At 72 h, bronchoalveolar lavage (BAL) leukocyte counts and protein concentration wer e determined, and lung tissue analysed for myeloperoxidase (MPO, a measure of PMN infiltration) and microscopic pathology. Analysis of BALs revealed a significant increase protein concentrations and in white blood cell and PM N infiltration (P < 0.05) following trauma. These acute changes were not ex acerbated by G-CSF, but were reversed by combined AICAR + G-CSF, which impl icates a physiologic role for adenosine. This suggests that combination the rapy may have beneficial effects on the lung after trauma.