Macrophage cyclooxygenase expression, immunosuppression, and cardiopulmonary dysfunction after blunt chest trauma.

BACKGROUND: Two series of experiments were performed in swine who received severe blunt chest trauma. The goals were to determine the time course of constitutive and inducible cyclooxygenase (COX) isozyme expression in pulmonary macrophages (Mphis), and to determine whether COX expression and cardiopulmonary dysfunction were altered when neutrophils (PMNs) were pharmacologically depleted with cyclophosphamide (CYC). METHODS: In series 1 (n = 17), anesthetized, mechanically ventilated swine were subjected to right chest trauma via captive bolt gun, hemorrhage, and a 60-minute shock period. In series 2 (n = 41), CYC (50 mg/kg intravenously) was administered 4 days before trauma, and the shock period was shortened to 30 minutes. In both series, hemodynamic support and supplemental oxygen were provided for an additional 60 to 90 minutes after shock. Mphis were isolated from serial bilateral bronchoalveolar lavages (BALs) and COX protein expression was measured with Western blots. RESULTS: In series 1, death occurred in 11 of 17. In survivors, Mphi COX-1 peaked at > 100 times baseline in both right BAL and left BAL by 60 minutes (before resuscitation). Changes in Mphi COX-2 were minimal. In series 2, before trauma, CYC (n = 16) reduced circulating and BAL PMNs by > 90% relative to control (n = 25, both p < 0.05) with no complicating side effects. After trauma, death occurred in 11 of 25 controls versus 9 of 16 with CYC. In survivors, PaO2/FIO2 was < 250 and PaCO2 was 25% higher on constant minute ventilation, indicating mismatched ventilation/perfusion; both changes were reduced with CYC (p < 0.05). In controls, bilateral histologic damage included edema, alveolar hemorrhage, and interstitial infiltrates. These changes were reduced by one third with CYC (p = 0.08). Trauma-induced changes in BAL protein, BAL elastase, or Mphi COX expression were not lessened by CYC. CONCLUSION: After unilateral chest trauma, Mphi COX-1, not COX-2, is induced bilaterally and before fluid resuscitation; CYC prevented PMN infiltration and attenuated structural and functional changes after resuscitation, which suggests that PMNs have a role in the pathogenic mechanism of secondary lung injury; Mphi COX expression and other injury markers were not altered by CYC; and since Mphis continued to express proinflammatory COX protein even after pretreatment with a powerful nonspecific immunosuppressant, and since there is residual alveolar capillary damage even in the absence of PMNs, it is logical to conclude that no single cell type or mediator is a practical therapeutic target and that novel resuscitation strategies must address multiple elements in the inflammatory cascade.

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.