Endotoxin-induced pulmonary vascular injury is mainly mediated by activated neutrophils in rats.
Acute respiratory failure is a common complication in patients with disseminated intravascular coagulation associated with sepsis. To elucidate the role of coagulation abnormalities in acute lung injury in sepsis, we investigated the effect of anticoagulants on the pulmonary vascular injury in rat induced by lipopolysaccharide (LPS). When administered intravenously, LPS (5 mg/kg body weight) significantly increased the accumulation of 111indium-labeled neutrophils in lung 30 min after administration. Subsequently, the pulmonary vascular permeability and the serum level of fibrin and fibrinogen degradation products (E) [FDP (E)] increased and remained elevated for several hours. Neither heparin alone, heparin plus antithrombin III, or dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa, a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury 6 hours after LPS administration, whereas these substances significantly inhibited the increase in serum FDP (E) at that time. LPS-induced pulmonary vascular injury was significantly attenuated in rats with methotrexate-induced leukocytopenia or treated with ONO-5046, a potent granulocyte elastase inhibitor, although ONO-5046 did not inhibit the LPS-induced increase in serum FDP (E). Thus, activated leukocytes play a more important role than coagulation abnormalities in the pathogenesis of LPS-induced pulmonary vascular injury in an experimental rat model of endotoxemia.
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D000990:Antithrombin III / Q000494:pharmacology / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects*; D003619:Dansyl Compounds / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D015951:Factor Xa / Q000187:drug effects; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D007275:Injections, Intravenous; D019272:Leukocyte Elastase; D007970:Leukopenia / Q000139:chemically induced / Q000150:complications; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000502:physiology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000097:blood / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000150:complications / Q000503:physiopathology*; D013047:Specific Pathogen-Free Organisms; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
D000590:Amino Acid Chloromethyl Ketones; D000925:Anticoagulants; D003619:Dansyl Compounds; D004731:Endotoxins; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D013449:Sulfonamides; C044101:endotoxin, Escherichia coli; C030824:dansylglutamyl-glycyl-arginine chloromethyl ketone; D000990:Antithrombin III; D006493:Heparin; C069195:sivelestat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D015951:Factor Xa; D005998:Glycine; D008727:Methotrexate