Thromboxane-blocked swine as an experimental model of severe intravascular inflammation and septic shock.
The cardiopulmonary response elicited by intravenous bacteria or endotoxin is well characterized in swine and has two major components. The first represents the acute pulmonary and broncho-constrictive phase (0-2 h) and the second phase (3-8 h) represents increased microvascular permeability, hypotension, and enhanced leukocyte-endothelial adhesion. The pulmonary vasoconstriction and bronchoconstriction of phase 1 results in acute pulmonary hypertension and airway dysfunction, which may result in rapid mortality. Because this acute pulmonary response may not mimic the development of human septic shock, we sought to block this early phase and examine the role of tumor necrosis factor in the latter septic phase (3-8 h). Employing a thromboxane A2 (TXA2) receptor antagonist (BAY U 3405) in the presence of LD100 Escherichia coli challenge, we blocked the acute pulmonary hypertensive phase and prevented early mortality, however, TXA2 blockade did not affect the latter development of septic shock and death. This latter lethal phase, characterized by prolonged leukopenia, was blocked in a dose-dependent manner by tumor necrosis factor monoclonal antibody. We conclude that the TXA2-blocked E. coli-challenged swine may provide a novel animal model in which to investigate the pathophysiology of acute septic shock.
Jesmok
G
G
Department of Pharmacology, Bayer Corp., West Haven, Connecticut 06516, USA.
Gundel
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002227:Carbazoles / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D007249:Inflammation / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects; D007970:Leukopenia / Q000382:microbiology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011652:Pulmonary Circulation / Q000187:drug effects; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology*; D013449:Sulfonamides / Q000627:therapeutic use*; D013552:Swine; D013928:Thromboxane A2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014661:Vasoconstriction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D002227:Carbazoles; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D013928:Thromboxane A2; C063119:ramatroban