Tumor necrosis factor-alpha primes pulmonary hemodynamic response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine.
We tested the hypothesis that tumor necrosis factor-alpha (TNF-alpha) primes the hemodynamic response to the neutrophil agonist N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in lungs isolated from guinea pigs. Lungs were isolated from animals 18 h after injection of TNF-alpha (3.20 x 10(5) U/kg ip). The infusion of FMLP (300 nM) into lungs isolated after the intraperitoneal administration of TNF-alpha resulted in increases in lung weight, lung (wet-dry)-to-dry weight ratio [(wet-dry)/dry wt], pulmonary capillary pressure, lung myeloperoxidase activity and perfusate thromboxane (Tx)B2 levels. Animals pretreated with the maximal possible amount of endotoxin in the TNF-alpha (1.7 pg endotoxin) did not respond to FMLP. WEB-2086 (37 microM), a platelet-activating factor (PAF) receptor antagonist, added to the perfusate attenuated the hemodynamic and TxA2 response to FMLP. Dazoxiben (0.5 mM), a TxA2 synthetase inhibitor, prevented the FMLP effect. Polyethylene glycol (PEG)-catalase (500 U/ml) added to the perfusate did not affect the FMLP response; however, PEG-catalase (10(5) U/kg) given intraperitoneally with the TNF-alpha decreased the synergism induced by TNF-alpha with FMLP. The data suggest that TNF-alpha primes the lung to the effects of FMLP by increasing the population of resident neutrophils in the lung and/or by in vivo oxidant generation. The pulmonary hemodynamic response and lung edema induced by FMLP are mediated by PAF and TxA2.
Johnson
A
A
Research Service, Veterans Affairs Medical Center, Albany, New York 12208.
Hocking
D C
DC
Ferro
T J
TJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004357:Drug Synergism; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D008168:Lung / Q000737:chemistry / Q000201:enzymology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009929:Organ Size; D009195:Peroxidase / Q000032:analysis; D010972:Platelet Activating Factor / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013928:Thromboxane A2 / Q000032:analysis / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D000975:Antioxidants; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D013928:Thromboxane A2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate