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 neutrop hil degranulation and margination, and increased vascular permeability are central to the pathophysiology of endotoxin-mediated acute lung i njury. Nonanticoagulant activities of low molecular weight heparin (LM WH) include solubilization of the TNF-alpha receptor protein, inhibiti on of neutrophil adhesion, and regulation of thromboxane B-2 (TXB2) bi osynthesis. In this study, we evaluated the ability of LMWH to modulat e TNF-alpha and TXB2 activity during endotoxemia and the subsequent ef fects on pulmonary hemodynamics. Domestic pigs 8-10 weeks old were ane sthetized and catheterized for standard cardiopulmonary measurements a nd the lungs harvested for cuff:vessel ratio, myeloperoxidase activity , and permeability index. Rigs were randomly assigned to one of four g roups: lipopolysaccharide (LPS) (n = 6), given.5 mu g/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 pl asma TNF-alpha and TXB2 activity; increased pulmonary arterial pressur e, 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 f rom those of the saline-treated control pigs. Pretreatment with LMWH a ttenuated the LPS-mediated TNF-alpha and TXB2 activity and attenuated LPS-mediated pulmonary hypertension, hypoxemia and neutrophil emigrati on, and edema formation. In conclusion, the data show that the protect ive effects of LMWH in this model of acute lung injury are associated with altered neutrophil adhesion and TNF-alpha and thromboxane activit y.