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Research Article Free access | 10.1172/JCI116351

Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation.

A C Windsor, C J Walsh, P G Mullen, D J Cook, B J Fisher, C R Blocher, S K Leeper-Woodford, H J Sugerman, and A A Fowler 3rd

Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.

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Published April 1, 1993 - More info

Published in Volume 91, Issue 4 on April 1, 1993
J Clin Invest. 1993;91(4):1459–1468. https://doi.org/10.1172/JCI116351.
© 1993 The American Society for Clinical Investigation
Published April 1, 1993 - Version history
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Abstract

Tumor necrosis factor (TNF alpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis. We examined the effects of pretreatment with a monoclonal antibody to TNF alpha on PMN function, hemodynamic derangements, and alveolar capillary membrane damage in a septic porcine model. Anti-TNF alpha profoundly improved hemodynamic consequences in this model. Reduction in PMN CD11/18 receptor expression, lung myeloperoxidase activity, and attenuation of peripheral neutropenia (all P < 0.05) indicate that pretreatment significantly reduced lung sequestration of PMNs seen in septic controls. In contrast, PMN oxygen radical (O2-) generation was not significantly different from unprotected septic animals. Despite the presence of circulating PMNs primed for O2- burst, alveolar capillary membrane damage, assessed by bronchoalveolar lavage protein content and arterial PO2 was markedly attenuated in the treatment group (P < 0.05). We conclude that anti-TNF alpha suppresses systemic hemodynamic actions of TNF alpha. Further, it prevents upregulation of PMN adhesion receptors inhibiting PMN/endothelial cell interaction. This prevents formation of a "microenvironment," protected from circulating oxidant scavengers, into which sepsis-activated PMNs release their toxic products. Pretreatment with anti-TNF alpha monoclonal antibody thus affords global protection in porcine Gram-negative sepsis.

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