Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: A potential clinical marker and mediator of severe sepsis*

Opal, Steven M.; Lim, Yow‐Pin; Siryaporn, Edward; Moldawer, Lyle L.; Pribble, John P.; Palardy, John E.; Souza, Sonia

doi:10.1097/01.ccm.0000253810.08230.83

Cited by 50 publications

(41 citation statements)

References 33 publications

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“…56 More recently, several GWAS of schizophrenia have consistently reported positive signals in the 3p21 region, particularly in the ITIH family of genes, 22,57,58 which codify for molecules that also seem to play an important role in inflammation. 59 Our genetic results show that other genes related to the TLR4 signalling pathway could also be involved in schizophrenia. Nominal associations were found for IL6 rs1800795 and IL1B rs1143634.…”

Section: E53mentioning

confidence: 68%

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

García‐Bueno

Gassó

MacDowell

et al. 2016

jpn

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Section: E53mentioning

confidence: 68%

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

García‐Bueno

Gassó

MacDowell

et al. 2016

jpn

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“…8, A, B, and D). A decrease of I␣I in plasma or serum has been associated with infectious disease and sepsis (32,(53)(54)(55). In lipopolysaccharide-treated mice, a model of sepsis, hepatic accumulation of HA⅐HC complexes has been observed (40), and HA⅐HC complexes have also been found in sera of patients with chronic liver disease associated with hepatitis virus infection (56).…”

Section: Discussionmentioning

confidence: 98%

Transfer of Inter-α-inhibitor Heavy Chains to Hyaluronan by Surface-linked Hyaluronan-TSG-6 Complexes

Colón

Shytuhina

Cowman

et al. 2009

Journal of Biological Chemistry

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Inter-␣-inhibitor, TSG-6, and hyaluronan have important functions in fertility and inflammation. Two subunits of inter-␣-inhibitor, the heavy chains, form covalent bonds with TSG-6 or hyaluronan in vitro. TSG-6-heavy chain complexes serve as intermediates in the transfer of heavy chains from inter-␣-inhibitor to hyaluronan. In vivo, in addition to these complexes, stable ternary complexes of hyaluronan with both TSG-6 and heavy chains have been demonstrated in the ovulatory cumulus oophorus. In our ongoing efforts to characterize the multiple interactions between hyaluronan, TSG-6 and inter-␣-inhibitor, we recently characterized the formation of highly stable complexes of TSG-6 with hyaluronan that had been tethered to a solid surface. Here we show that these hyaluronan-TSG-6 complexes are functionally active and transfer heavy chain subunits from inter-␣-inhibitor to either free or surface-bound hyaluronan. Transitional hyaluronan-TSG-6-heavy chain complexes do not accumulate in vitro. Our data show the capability for heavy chain transfer by both free TSG-6 and preformed hyaluronan-TSG-6 complexes, suggesting that both might contribute to hyaluronan modification in vivo. Transfer of heavy chains to surface-tethered hyaluronan by either free TSG-6 or surface-tethered hyaluronan-TSG-6 complexes did not affect the CD 44-mediated binding of BW 5147 cells in vitro. We show how TSG-6 and hyaluronan together can deplete inter-␣-inhibitor and generate bikunin, as has been observed in sepsis, and discuss the role of TSG-6 in the generation of hyaluronan-heavy chain complexes associated with ovulation, arthritis, and sepsis.

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“…Ulinastatin and members of the IaI family are also considered as candidate biomarkers for diagnosis and prognosis of sepsis [12], but for some reason no clinical studies appear to have been done in Western countries to date. A clintrials.gov trial search revealed nine registered studies with ulinastatin, mainly focusing on cardiac surgery and ARDS, and none on sepsis treatment.…”

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confidence: 99%

An exciting candidate therapy for sepsis: ulinastatin, a urinary protease inhibitor

Linder

Russell

2014

Intensive Care Med

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In a recent issue of Intensive Care Medicine (ICM), Karnad et al. [1] reported a randomized, double-blind, placebo-controlled multicenter trial (RCT) evaluating the efficacy of a urinary protease inhibitor (ulinastatin) compared to placebo in patients with severe sepsis. This RCT was conducted in the intensive care units (ICUs) of seven tertiary care hospitals in India including 114 patients. Patients received intravenous ulinastatin or placebo twice daily for 5 days. Ulinastatin was associated with significantly decreased mortality (7.3 vs. 20.3 %, P = 0.042), with 25 % of the deaths in the ulinastatin group judged related to ARDS compared to 42 % in the placebo group, lower frequency of new organ dysfunction, and shorter durations of mechanical ventilation and hospital stay compared to placebo. Furthermore, in stepwise multiple logistic regression (adjusted for age, gender, GCS, specific organ failures, number of organ failures, need for vasopressor, and mechanical ventilation), treatment with ulinastatin was associated with a statistically significant decrease in mortality.This is an interesting trial with quite impressive results given the relatively small sample size, which raises these questions: what is ulinastatin and why might it be important in sepsis?Ulinastatin (UTI) is a multifunctional Kunitz-type serine protease inhibitor found in human urine and blood. UTI (also known as ulinastatin, HI-30, ASPI, or bikunin) is produced by hepatocytes and belongs to a group of proteins known as the inter-a-inhibitor (IaI) family. During inflammation, ulinastatin is cleaved from IaI family proteins through proteolytic cleavage by neutrophil elastase in the peripheral circulation or at sites of inflammation. Ulinastatin inhibits various serine proteases that are important in the pathophysiology of sepsis including trypsin, thrombin, chymotrypsin, kallikrein, plasmin, elastase, cathepsin, and factors IXa, Xa, XIa, and XIIa. Ulinastatin also inhibits inflammation by suppressing the infiltration of neutrophils and release of elastase and inflammatory mediators from neutrophils. Ulinastatin also inhibits the production of TNF-a, IL-1, and IL-6 possibly through suppression of MAPK signalling pathway [2].The RCT of Karnad and colleagues in ICM supports previous clinical trials of ulinastatin (Table 1). A recent systematic review and meta-analysis found 29 RCTs of ulinastatin in ARDS with more than 1,700 participants. Even though the authors concluded that most studies were of poor quality they found that ulinastatin decreased ICU mortality, improved oxygenation, and decreased duration of hospital stay [3]. Clinically ulinastatin is already in use, for instance in Japan, to treat acute pancreatitis (postendoscopic retrograde cholangiopancreatography pancreatitis), in which proteases play a pathophysiological role. Other clinical conditions for which ulinastatin has been evaluated clinically are ''systemic inflammatory response

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Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: A potential clinical marker and mediator of severe sepsis*

Abstract: Inter-alpha inhibitor proteins are markedly reduced in severe sepsis, and failure of recovery of IalphaIp levels over the course of sepsis is associated with an unfavorable outcome.

Cited by 50 publications

References 33 publications

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

Transfer of Inter-α-inhibitor Heavy Chains to Hyaluronan by Surface-linked Hyaluronan-TSG-6 Complexes

An exciting candidate therapy for sepsis: ulinastatin, a urinary protease inhibitor

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