title: 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.
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.
authors.affiliation: Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0519.
authors.forename: A C
authors.initials: AC
authors.lastname: Windsor
authors.forename: C J
authors.initials: CJ
authors.lastname: Walsh
authors.forename: P G
authors.initials: PG
authors.lastname: Mullen
authors.forename: D J
authors.initials: DJ
authors.lastname: Cook
authors.forename: B J
authors.initials: BJ
authors.lastname: Fisher
authors.forename: C R
authors.initials: CR
authors.lastname: Blocher
authors.forename: S K
authors.initials: SK
authors.lastname: Leeper-Woodford
authors.forename: H J
authors.initials: HJ
authors.lastname: Sugerman
authors.forename: A A
authors.initials: AA
authors.lastname: Fowler
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D005609:Free Radicals; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen