Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model.
Tumor necrosis factor alpha (TNF-alpha) activity, platelet and neutrophil degranulation and margination, and increased vascular permeability are central to the pathophysiology of endotoxin-mediated acute lung injury. Nonanticoagulant activities of low molecular weight heparin (LMWH) include solubilization of the TNF-alpha receptor protein, inhibition of neutrophil adhesion, and regulation of thromboxane B2 (TXB2) biosynthesis. In this study, we evaluated the ability of LMWH to modulate TNF-alpha and TXB2 activity during endotoxemia and the subsequent effects on pulmonary hemodynamics. Domestic pigs 8-10 weeks old were anesthetized and catheterized for standard cardiopulmonary measurements and the lungs harvested for cuff:vessel ratio, myeloperoxidase activity, and permeability index. Pigs were randomly assigned to one of four groups: lipopolysaccharide (LPS) (n = 6), given .5 microg/kg/h Escherichia coli LPS intravenously for 6 h; saline control (n = 5); LMWH (n = 5), given .5 mg/kg LMWH for 30 min, followed by .5 mg/kg/h; and LMWH + LPS (same dosages, n = 6). Administration of LPS resulted in increased plasma TNF-alpha and TXB2 activity; increased pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen tension; decreased systemic arterial oxygen tension; and pulmonary edema. The cardiopulmonary parameters for the LMWH-treated pigs did not differ from those of the saline-treated control pigs. Pretreatment with LMWH attenuated the LPS-mediated TNF-alpha and TXB2 activity and attenuated LPS-mediated pulmonary hypertension, hypoxemia and neutrophil emigration, and edema formation. In conclusion, the data show that the protective effects of LMWH in this model of acute lung injury are associated with altered neutrophil adhesion and TNF-alpha and thromboxane activity.
Darien
B J
BJ
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison 53706, USA. darienb@svm.vetmed.wisc.edu
Fareed
J
J
Centgraf
K S
KS
Hart
A P
AP
MacWilliams
P S
PS
Clayton
M K
MK
Wolf
H
H
Kruse-Elliott
K T
KT
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D019446:Endotoxemia / Q000097:blood / Q000503:physiopathology* / Q000517:prevention & control*; D004731:Endotoxins / Q000633:toxicity; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006487:Hemostasis; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D055370:Lung Injury; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013929:Thromboxane B2 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects
D004731:Endotoxins; D006495:Heparin, Low-Molecular-Weight; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D009195:Peroxidase