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.


CONCLUSIONS
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.
Desselle
W J
WJ
Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee , USA.
Greenhaw
J J
JJ
Trenthem
L L
LL
Fabian
T C
TC
Proctor
K G
KG
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003520:Cyclophosphamide / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000097:blood*; D019272:Leukocyte Elastase / Q000097:blood; D008168:Lung / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D012151:Resuscitation; D013552:Swine; D013898:Thoracic Injuries / Q000276:immunology* / Q000473:pathology; D014949:Wounds, Nonpenetrating / Q000276:immunology* / Q000473:pathology
D007166:Immunosuppressive Agents; D007527:Isoenzymes; D003520:Cyclophosphamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019272:Leukocyte Elastase