A RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA P80 RECEPTOR - FC FUSION PROTEIN DECREASES CIRCULATING BIOACTIVE TUMOR-NECROSIS-FACTOR-ALPHA BUT NOT LUNG INJURY OR MORTALITY DURING IMMUNOSUPPRESSION-RELATED GRAM-NEGATIVE BACTEREMIA

Purpose: During gram-negative bacteremia (GNB), tumor necrosis factor- alpha (TNF-alpha) is a critical early mediator of host defense, whose overexpression can initiate acute lung injury, multiple organ failure, and death. In this study we evaluated the ability of a chimeric fusio n protein containing two extracellular domains of the human p80 TNF-al pha receptor and the Fc region of human IgG(1) (TNFR:Fc) to reduce cir culating TNF-alpha, and to ameliorate organ injury and improve surviva l in a rodent model of GNB during immunosuppression-related neutropeni a. Materials and Methods: Conscious catheterized male rats (n = 37) wi th stable cyclophosphamide-induced neutropenia were infected intraveno usly (IV) with 5 x 10(9) live Escherichia coli (EC, serotype O55:B5) e nding at t = 0. All animals received antibiotics (penicillin/amikacin sulfate) at t = 0.5 and t = 8 hours, and 0.9% sodium chloride (normal saline solution (NS), 1 mL/h) from t = 0 to 8 hours. Subgroups were po st-treated at t = 0.5 hours with a 1.0 mL IV dose of TNFR:Fc (60, 600, or 1,200 mu g; Immunex), 600 mu g of human IgG1-kappa or IgG1-lambda (Sigma), or NS alone (controls). A separate TNFR:Fc pretreatment subgr oup received 600 mu g/rat of the fusion protein 5 minutes before start ing EC infusion. Hemodynamics were monitored continuously through t = 24 hours, and arterial samples were collected at baseline and at t = 1 .5, 4.5, 8, and 24 hours after EC were analyzed for blood gases, quant itative culture, serum endotoxin, bioactive and antigenic TNF-alpha, a nd formed elements. Postmortem tissues were examined for histopatholog ic changes. Results: Compared with antibiotic-treated and fluid-suppor ted controls, TNFR:Fc dose-dependently reduced bioactive but not antig enic TNF-alpha without altering bacterial clearance, serum endotoxin, or 24-hour survival. Of note, 600 mu g of IgG1-kappa or IgG1-lambda at tenuated peak bioactive TNF-alpha to a similar degree as 1,200 mu g TN FR:Fc, and also significantly reduced serum endotoxin levels. Neverthe less, by t = 8 hours all bacteremic rats were hypothermic with tachypn ea-related hypocarbia and hyperoxemia and were thrombocytopenic. At de ath, all subgroups showed similar hepatic glycogen depletion and pulmo nary congestion with perivascular edema and alveolar hemorrhage. Concl usions: Although TNFR:Fc and its idiotypic control IgG1 reduced circul ating bioactive TNF-alpha, neither treatment prevented progression of lethal shock with attendant organ injury in this conscious, antibiotic -treated and fluid-resuscitated model of immunosuppression-related GNB . Copyright (C) 1997 by W.B. Saunders Company.