Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis

Abstract

Objective: To ascertain the effect of delayed tumor necrosis factor alpha (TNF-alpha) on the evolution of systemic and pulmonary injury after the onset of sepsis.

Design: Prospective controlled trial.

Intervention: Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti-TNF-alpha monoclonal antibody (5 mg/kg). Control animals received 0.9% saline.

Results: Delayed anti-TNF-alpha treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P < .05 by t test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (+/- SEM) plasma lactate levels at 5 hours compared with baseline values (3.8 +/- 0.7 vs 2 +/- 0.4, P < .05), but remained unchanged from baseline following anti-TNF-alpha treatment (1.5 +/- 0.1 vs 1.6 +/- 0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti-TNF-alpha treatment and was associated with downregulation (P < .05 by t test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P < .05 by t test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (+/- SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti-TNF-alpha animals (septic animals at 5 hours compared with baseline value, 1044 +/- 270 vs 149 +/- 28 micrograms/mL; control animals at 5 hours compared with baseline value, 217 +/- 83 vs 129 +/- 19 micrograms/mL; P < .05 by t test and analysis of variance).

Conclusions: These data show that delayed anti-TNF-alpha treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti-TNF-alpha treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti-TNF-alpha treatment in clinical practice.