COMBINED IBUPROFEN AND MONOCLONAL-ANTIBODY TO TUMOR-NECROSIS-FACTOR-ALPHA ATTENUATE HEMODYNAMIC DYSFUNCTION AND SEPSIS-INDUCED ACUTE LUNG INJURY

A number of key mediators are implicated in the pathophysiology of sepsis. In previous studies of a septic porcine model, ibuprofen pretreatment prevented the early but not the late rise in pulmonary vascular resistance index (PVRI) and the early but not the late fall in arterial PO2 (PaO2), whereas monoclonal antibody to tumor necrosis factor alpha (anti-TNFalpha) prevented the late but not the early rise in PVRI and the late but not the early fall in PaO2. This study examined the impact of pretreatment with combined ibuprofen and anti-TNF-alpha on the course of sepsis and acute lung injury (ALI) in pigs. Three groups were studied for 5 hours. Groups I (n = 9) and II (n = 5) received a 1-hour infusion of Pseudomonas aeruginosa. Group II received ibuprofen (12.5 mg/kg) and anti-TNF-alpha (5 mg/kg) before P. aeruginosa, and a further bolus of ibuprofen at 120 minutes. Group III (n = 11) received sterile saline. Group I demonstrated a significant (p < 0.05) rise in plasma TNF-alpha that was abolished in group II. The SVRI in group II did not change significantly from baseline through the study and the SVRI rose sharply in group I following onset of the infusion of P. aeruginosa, as did PVRI. There was no significant change in PVRI from baseline in group II, except for the final 60 minutes; PVRI in group II was significantly less than in group I throughout the study. The protein (BAL-P) and neutrophil (BAL) contents in bronchoalveolar lavage fluid in group II were significantly less than in group I at the study conclusion. However, neutrophil superoxide production in group II at 300 minutes was not attenuated. In conclusion, combined ibuprofen and anti-TNF-alpha moderate the hemodynamic response to sepsis and offer greater protection against acute lung injury than either agent used alone. The loss of ibuprofen-mediated inhibition of neutrophil superoxide generation represents a significant interaction between these agents that warrants further investigation.