Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain

Shinmoto, Hiroshi; Onogi, Akira; Kajiwara, Hirotaka; Yoshida, Shozo; Furukawa, Naoto; Shoji, Hirokazu; Tanase, Yasuhito; Kanayama, Seiji; Noguchi, Taketoshi; Yamada, Yoshihiko; Oi, Hidekazu; Kobayashi, Hiroshi

doi:10.1007/s00011-010-0205-5

Cited by 65 publications

(42 citation statements)

References 81 publications

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“…Bikunin is a Kunitz-type protease inhibitor [11] and a structural component of extracellular matrix [12]. Bikunin is the common subunit of a group of protein/carbohydrate complexes that constitute plasma proteins of the inter--inhibitor family [13].…”

Section: Expressionmentioning

confidence: 99%

A1M, an extravascular tissue cleaning and housekeeping protein

Åkerström¹,

Gram²

2014

Free Radical Biology and Medicine

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Section: Expressionmentioning

confidence: 99%

A1M, an extravascular tissue cleaning and housekeeping protein

Åkerström¹,

Gram²

2014

Free Radical Biology and Medicine

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“…To counter-regulate the effect of these proteases, several protease inhibitors are produced by the liver in the presence of inflammation; these include acute phase reactants such as α 1 -antitrypsin and proteins of the inter-α-inhibitor family [9]. Urinary trypsin inhibitor is one such important protease inhibitor found in human blood and urine; it has been also referred to in the literature as ulinastatin or bikunin [10, 11]. It is an acidic glycoprotein (molecular weight 30 kDa) and Kunitz-type serine protease inhibitor composed of 143 amino acid residues and includes two Kunitz-type domains [7, 10].…”

Section: Introductionmentioning

confidence: 99%

“…As compared to wild-type mice, mortality due to experimental sepsis is higher in genetically modified knockout mice that lack the genes for synthesis of urinary trypsin inhibitor [11, 13]. Several preclinical studies have shown a reduction in the systemic inflammatory response and organ dysfunction due to sepsis in animals treated with ulinastatin [13–17].…”

Section: Introductionmentioning

confidence: 99%

Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study

Karnad¹,

Bhadade

Verma

et al. 2014

Intensive Care Med

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PurposeUlinastatin, a serine protease inhibitor, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality in experimental sepsis. We studied the effect of ulinastatin on 28-day all-cause mortality in a double-blind trial in patients with severe sepsis in seven Indian hospitals.MethodsPatients with sepsis were randomized within 48 h of onset of one or more organ failures to receive intravenous administration of ulinastatin (200,000 IU) or placebo 12 hourly for 5 days.ResultsOf 122 randomized subjects, 114 completed the study (55 receiving ulinastatin, 59 receiving placebo). At baseline, the mean APACHE II score was 13.4 (SD = 4.4), 48 (42 %) patients were receiving mechanical ventilation, 58 (51 %) were on vasopressors, and 35 % had multiple organ failure. In the modified intention-to-treat analysis (patients receiving six or more doses of study drugs), 28-day all-cause mortality was 7.3 % with ulinastatin (4 deaths) versus 20.3 % (12 deaths) with placebo (p = 0.045). On multivariate analysis too, treatment with ulinastatin (odds ratio 0.26, 95 % CI 0.07–0.95; p = 0.042) independently decreased 28-day all-cause mortality. However, the mortality difference did not reach statistical significance in the intention-to-treat analysis [10.2 % (6/59 deaths) with ulinastatin versus 20.6 % (13/63 deaths) in the placebo group; p = 0.11]. The ulinastatin group had lower incidence of new-onset organ failure (10 vs. 26 patients, p = 0.003), more ventilator-free days (mean ± SD 19.4 ± 10.6 days vs. 10.2 ± 12.5 days, p = 0.019), and shorter hospital stay (11.8 ± 7.1 days vs. 24.2 ± 7.2 days, p < 0.001).ConclusionsIn this pilot study, intravenous administration of ulinastatin reduced mortality in patients with severe sepsis in the modified intention-to-treat analysis, but not in the intention-to-treat analysis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-014-3278-8) contains supplementary material, which is available to authorized users.

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“…Ulinastatin is one a serine protease inhibitor in the multifunctional Kunitz family found in human blood and urine 3. Basic research showed that ulinastatin had anti‐inflammatory activity through suppressing neutrophil accumulation and activation and inhibiting secretion of inflammatory cytokines 3.…”

Section: Introductionmentioning

confidence: 99%

“…Basic research showed that ulinastatin had anti‐inflammatory activity through suppressing neutrophil accumulation and activation and inhibiting secretion of inflammatory cytokines 3. Clinical studies also reported that anti‐inflammatory activity of ulinastatin decreased the mortality of SIRS conditions, such as sepsis4, 5 and acute respiratory distress syndrome 6.…”

Section: Introductionmentioning

confidence: 99%

Ulinastatin did not reduce mortality in elderly multiple organ failure patients: a retrospective observational study in a single center ICU

Uchida

Abe

Ono

et al. 2017

Acute Medicine & Surgery

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AimOur aim was to evaluate the effect of ulinastatin on 28‐day mortality in patients who developed multiple organ failure (MOF) related to their acute illness and were admitted to the intensive care unit (ICU).MethodsWe carried out a retrospective observational study of MOF patients in a general ICU of a tertiary care hospital in Japan from January 2009 to December 2012. The primary outcome was 28‐day all‐cause mortality. Secondary outcomes were ventilator‐free days, ICU‐free days, and vasopressor‐free days at day 28. We investigated the association between ulinastatin treatment and outcomes using multivariable regression analysis.ResultsA total of 212 MOF patients were included, 79 (37%) of whom received ulinastatin. The median age was 70 years (interquartile range, 60–77) and median APACHE II score was 25 (interquartile range, 19–29). Overall 28‐day mortality was 20%. There were no significant differences between the ulinastatin group and the control group in age, gender, or APACHE II score. The ulinastatin group had higher prevalence of sepsis (44% versus 22%, P = 0.001). Multivariable logistic regression analysis showed that ulinastatin was not associated with 28‐day mortality (odds ratio = 1.22; 95% confidence interval, 0.54–2.79). Moreover, ulinastatin did not reduce the mortality in patients with sepsis (odds ratio = 1.92; 95% confidence interval, 0.52–7.13). However, ICU‐free days and ventilator‐free days was significantly fewer in the ulinastatin group than control group.ConclusionsIn this retrospective observational study, ulinastatin was not associated with mortality in elderly patients with established MOF, although it might be related to patient's utility.

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Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain

Abstract: Recent studies have demonstrated that the Kunitz inhibitors are not only protease inhibitors, but can also prevent inflammation and tissue injury and subsequently promote tissue remodeling.

Cited by 65 publications

References 81 publications

A1M, an extravascular tissue cleaning and housekeeping protein

A1M, an extravascular tissue cleaning and housekeeping protein

Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study

Ulinastatin did not reduce mortality in elderly multiple organ failure patients: a retrospective observational study in a single center ICU

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