Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes.
BACKGROUND
The acute respiratory distress syndrome (ARDS) is often caused by fat tissue embolism. One of the most common animal models of ARDS is produced by direct administration of oleic acid (OA). Activated leukocytes are critically involved in the pathological mechanism in this model. Human urinary trypsin inhibitor (UTI) is known to inhibit production of tumor necrosis factor (TNF)-alpha, which potently stimulates leukocyte activation. The purpose of this study was to clarify whether UTI improves OA-induced lung injury in rats by inhibiting activated leukocytes via TNF-alpha production.


METHODS
Rats were subjected to a single intravenous administration of OA into the pedicle vein. Acute lung injury was evaluated by arterial blood gases and histological changes in lungs. Pulmonary vascular permeability, accumulation of neutrophils, and the levels of TNF-alpha in lung tissues were also examined. Rats were divided into four experimental groups: a sham operated, OA, OA + UTI, and OA + nitrogen mustard (NM)-induced leukocytopenia group. UTI was intravenously administered 30 min before OA administration. Leukocytopenia was induced by the administration of NM.


RESULTS
UTI significantly improved the OA-induced histological changes for 4 h after OA administration. The OA-induced reduction of PaO2, the increase of pulmonary vascular permeability, and the levels of MPO activity and TNF-alpha in lung tissues were significantly improved in rats administrated UTI. The effects in the leukocytopenia group were similar to those in the UTI-administered group.


CONCLUSIONS
Leukocytes play a critical role in the development of OA-induced lung injury. It was suggested that UTI contributed to the reduction in the OA-induced lung injury by inhibiting TNF-alpha and thereby suppressing leukocyte.
Ito
Koji
K
Department of Anesthesiology, Faculty of Medicine, Oita University, Idaigaoka, Hasama-machi, Oita 879-5593, Japan. kitoh@med.oita-u.ac.jp
Mizutani
Akio
A
Kira
Shinitiro
S
Mori
Masakazu
M
Iwasaka
Hideo
H
Noguchi
Takayuki
T
D000208:Acute Disease; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000008:administration & dosage*; D007275:Injections, Intravenous; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007970:Leukopenia / Q000276:immunology; D008297:Male; D019301:Oleic Acid; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014361:Trypsin Inhibitors / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006023:Glycoproteins; D014361:Trypsin Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019301:Oleic Acid; D009195:Peroxidase; C028665:urinastatin