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.
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.
Windsor
A C
AC
Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.
Walsh
C J
CJ
Mullen
P G
PG
Cook
D J
DJ
Fisher
B J
BJ
Blocher
C R
CR
Leeper-Woodford
S K
SK
Sugerman
H J
HJ
Fowler
A A
AA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018845:CD11 Antigens; D018821:CD18 Antigens; D005609:Free Radicals; D009504:Neutrophils / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D010100:Oxygen / Q000097:blood*; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*; D018805:Sepsis / Q000503:physiopathology*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D005609:Free Radicals; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen