Endogenous adenosine and secondary injury after chest trauma.

BACKGROUND: No previous studies have examined actions of adenosine or related compounds after blunt chest trauma, but we have shown that the prototype adenosine-regulating agent, acadesine (aminoimidazole carboxamide ribonucleotide [AICAR]), has multiple favorable anti-inflammatory actions after other forms of trauma, ischemia, hemorrhage, and sepsis; and that a progressive inflammatory response in the contralateral (uninjured) lung after unilateral blunt chest trauma is caused (in part) by activation and sequestration of circulating leukocytes (white blood cells [WBCs]). Thus, we hypothesized that AICAR would ameliorate WBC-dependent, secondary pathophysiologic changes after blunt chest trauma. METHODS: Mongrel pigs (28+/-1 kg, n = 21) were anesthetized, mechanically ventilated, and injured on the right chest (pulmonary contusion) with a captive bolt gun. Either AICAR (1 mg/kg + 0.2 mg/kg/min) or its saline vehicle were administered for a 12-hour period, beginning 15 minutes before injury. RESULTS: Injury caused a three- to fourfold increase in bronchoalveolar lavage (BAL) WBC counts, 10- to 20-fold increases in BAL protein, and 200% increases in lung edema as measured by wet-dry ratio (all p < 0.05), in both the injured (right) and the noninjured (left) lungs. With AICAR versus saline, BAL WBC counts, lung myeloperoxidase levels, and systemic hemodynamics were similar. However, the increases in BAL protein were attenuated by 30% to 50% (p < 0.14, NS) and edema was reduced (p < 0.05) in both lungs. Furthermore, oxygenation, hypercapnia, acidosis (all p < 0.05), and survival were improved (9 of 10 vs. 4 of 11, p < 0.04). CONCLUSION: Pretreatment with AICAR before experimental pulmonary contusion ameliorates the trauma-induced destruction of the alveolar capillary membrane, and attenuates the delayed secondary injury in the contralateral uninjured lung, by a mechanism that may be independent of leukocytes. Endogenous adenosine could have a role in the pathophysiologic response after blunt chest injury, with potential sites of action including the endothelium and alveolar macrophage. Adenosine-regulating agents may have therapeutic potential after blunt chest injury, but further studies are needed in clinically relevant models, with administration begun at the time of resuscitation.

Acadesine and intestinal barrier function after hemorrhagic shock and resuscitation.

OBJECTIVE: To determine actions of the prototype adenosine-regulating agent, acadesine (5-amino-1-[beta-D-ribofuranosyl]imidazole-4-carboxamideriboside; AICAR), on intestinal barrier function after hemorrhagic shock and fluid resuscitation, three series of experiments were performed to measure functional (series 1: intestinal permeability and intramural blood flow), structural (series 2: histology), and biochemical (series 3: tissue concentrations of adenine nucleotides and metabolites) changes. DESIGN: Prospective, controlled animal study. SETTING/SUBJECTS: University laboratory; juvenile crossbred pigs of either gender. INTERVENTIONS: Either AICAR or its saline vehicle were intravenously administered 30 mins before 40% hemorrhage. After 1 hr shock, shed blood plus crystalloid was administered for resuscitation. Data were collected for 1 hr thereafter. MEASUREMENTS AND MAIN RESULTS: In series 1, permeability of the ileum was measured by assaying the portal venous concentration of fluorescein-labeled dextran after placement of this tracer in the lumen. In addition, serosal and mucosal blood flow were monitored with laser-Doppler probes. With vehicle, hemorrhage and resuscitation increased the dextran concentration three-fold and decreased blood flow 50% of the baseline values (both p < .05). AICAR attenuated the permeability increase (p < .05) and attenuated mucosa, but not serosal, ischemia (p < .05). Similar effects were observed with a structurally dissimilar compound-- 4-amino-1-(5-amino-5-deoxy-1-beta-D-ribofuranosyl)-3-bromo-pyrazolo [3,4-d] pyrimidine, a specific adenosine kinase inhibitor-as well as continuous intra-arterial infusion of adenosine. In series 2, AICAR ameliorated the mucosal damage caused by shock/resuscitation (p < .05). In series 3, AICAR increased ileal tissue adenine nucleotides and metabolites during the shock period (p < .05). CONCLUSIONS: AICAR attenuated gut permeability changes, increased mucosal perfusion, and increased tissue adenine nucleotides, which is consistent with preserved intestinal barrier function after hemorrhage and fluid resuscitation. In context with previous studies from this laboratory, these results provide further evidence for a role for adenosine as an endogenous anti-inflammatory autacoid after shock and trauma. Further study is needed to determine the therapeutic potential of adenosine-regulating agents in resuscitation fluids.