Ulinastatin, an Elastase Inhibitor, Inhibits the Increased mRNA Expression of Prostaglandin H₂Synthase–Type 2 in Kawasaki Disease

Abstract

Kawasaki disease is an inflammatory disease of unknown cause that causes panvasculitis, including coronary arteritis. Polymorphonucleocytosis in the early stage of the illness suggests the implication of neutrophils in the pathogenesis of the disease. In the acute phase of Kawasaki disease, mRNA expression of prostaglandin H2 synthase (PHS)-2, as determined by reverse transcription-polymerase chain reaction, was markedly enhanced, and thromboxane A2 (TXA2)-synthesizing activity was increased in polymorphonuclear leukocytes (PMNL). This up-regulation of PHS-2 was suppressed by ulinastatin (a neutrophil-elastase inhibitor) treatment. Lipopolysaccharide-induced enhancement of PHS-2 mRNA was also inhibited by therapeutic doses of ulinastatin in vitro by use of PMNL from healthy volunteers. Thus, ulinastatin inhibits arachidonate PHS metabolism by inhibiting new induction of PHS-2 at the mRNA level, which is a novel pharmacologic action of this substance. Ulinastatin treatment is possibly an additional therapeutic approach to Kawasaki disease.

Enhanced iNOS Expression in Leukocytes and Circulating Endothelial Cells Is Associated with the Progression of Coronary Artery Lesions in Acute Kawasaki Disease

“…Although we could not demonstrate the infiltration of neutrophils in the coronary artery wall, a previous pathologic study confirmed (6). Recently, treatment with a neutrophil-elastase inhibitor, ulinastatin, was reported to be a potential adjunct to ␥-globulin therapy in acute KD (22). iNOS expression in neutrophils may reflect their activation and enhanced function in the early phase of acute KD, as reported previously (23).…”

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association

“…This 67 000-Dalton glycoprotein inhibits neutrophil elastase as well as prostaglandin H2 synthase at the messenger RNA level. 175 Ulinastatin has been proposed as useful in IVIG-refractory patients, 175 but its effectiveness is unproven, and additional experience with this agent is necessary before it can be recommended (evidence level C).…”

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease

“…This 67 000-Da glycoprotein inhibits neutrophil elastase as well as prostaglandin H2 synthase at the messenger RNA level. 175 Ulinastatin has been proposed as useful in IVIG-refractory patients, 175 but its effectiveness is unproven and additional experience with this agent is necessary before it can be recommended (evidence level C).…”