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).


CONCLUSIONS
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.
Davis
K A
KA
Department of Surgery, University of Tennessee, Memphis, USA. kdavis3@luc.edu
Fabian
T C
TC
Ragsdale
D N
DN
Trenthem
L L
LL
Proctor
K G
KG
D000138:Acidosis / Q000209:etiology; D000241:Adenosine / Q000276:immunology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects; D006935:Hypercapnia / Q000209:etiology; D007249:Inflammation; D007958:Leukocyte Count; D009195:Peroxidase / Q000032:analysis; D012263:Ribonucleosides / Q000276:immunology / Q000627:therapeutic use*; D016019:Survival Analysis; D013552:Swine; D013898:Thoracic Injuries / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D014949:Wounds, Nonpenetrating / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology
D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D009195:Peroxidase; D000241:Adenosine