Naslov
Decreased inter-alpha inhibitor plasma levels in septic patients and increased survival upon one dose treatment in animal sepsis models

Autori
Bendelja, Krešo ; Lim, Yow-Pin ; Wang, Ping ; Opal, Steven ; Josić, Đuro ; Hixson, Douglas

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Knjiga sažetaka / - , 2004

Skup
Godišnji sastanak Hrvatskog imunološkog društva, 2004

Mjesto i datum
Opatija, Hrvatska, 08.10.2004. - 10.10.2004

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
severe sepsis; E. coli; inter-alpha inhibitor

Sažetak
Inter-alpha (I I) inhibitor belongs to a family of plasma protease inhibitors known as serpins that poses exclusive inhibitory activity toward serine proteases. I I is a complex glycoprotein (Mr. 230, 000) present in human plasma. It is composed of who heavy polypeptide chains (HC1 and HC2) covalently bound to a light polypeptide chain (LC) over glycosaminoglycan bridge. LC (bikunin) displays inhibitory potential towards certain serine proteases like elastase, plasmin and cathepsin G that are unspecific inflammatory mediators. Those proteases generally contribute to I I degradation resulting in a release of LC, with preserved inhibitory activity. Bikunin is rapidly removed from the circulation by the urine. In our lab we have developed monoclonal antibody that recognizes LC that allowed us to measure plasma I I levels in patients with sepsis. We have analyzed 52 patient plasma samples and 10 plasma obtained from the healthy controls. I I levels are decreased during sepsis (overall 20-90% from the median control levels). Nevertheless, significant decrease in I I levels significantly correlates with endotoxin shock finding and finally with the mortality index. . Decreased I I levels in patients with sepsis address possible therapeutic value of I I. We have tested possible impact of purified human IaI on survival in vivo in two different experimental animal sepsis models. Caecal ligation and puncture (CLP) was performed on rats and single dose of I I was administered (30 mg/kg of body weight) with a 1 hour delay. Animals in a treated group showed significant improvement in a survival index (89% vs. 30% of control group). Adult mice were infected with a high dose of live E. coli subcutaneously and 2 hours after, animals received single dose of I I (30 mg/kg) combined with antibiotic Rocephin. Overall, survival has increased in a treated group compared to group that received human albumin instead (46% vs. 12%). Deleterious effect of TNF-alpha (TNF- ) in systemic and local inflammatory reactions is well known. Therefore, we have tested possible anti-inflammatory effect of I I on TNF- synthesis in vitro. Purified human I I decreased TNF- secretion upon lipopolisacharide (LPS) stimulation of THP-1 cells. This anti-inflammatory effect is dose (LPS) and time dependent. Conclusions During sepsis plasma IaI is consumed resulting in decreased inhibitor level moreover in patients with circulatory failure (endotoxin shock) ; administration of purified human I I can correct balance between plasma proteases and inhibitors, decrease pro-inflammmatoy TNF- cytokine secretion and finally significantly increase a survival among patients with severe sepsis.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Kliničke medicinske znanosti

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