Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis
A. C. Windsor, P. G. Mullen, C. J. Walsh, B. J. Fisher, C. R. Blocher, G. Jesmok, A. A. Fowler 3rd and H. J. Sugerman
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond.
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.
