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

Abstract

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

Trends in sepsis mortality over time in randomised sepsis trials: a systematic literature review and meta-analysis of mortality in the control arm, 2002–2016

“…However, two of these interventions, which used selenium and talactoferrin respectively, failed to demonstrate any benefit when replicated in larger studies with multicentre settings [41,42]. The other two treatment strategies with proven efficacy (esmolol and ulinastatin) [24,25] have not yet been implemented in the guidelines for standard care of sepsis, as their clinical effect needs further evaluation, although ulinastatin has been described as a promising novel treatment option [43]. Our subgroup analysis of the interventions and their effect on mortality revealed a significant increase in relative risk in the group of interventions categorised as "modulation of coagulation and inflammation".…”

Glabridin attenuates lipopolysaccharide-induced acute lung injury by inhibiting p38MAPK/ERK signaling pathway

“…Increasing permeability of alveolar capillary results in two-way leakage of the intravascular macromolecules and SP [16]. Polymorphonuclear leukocytes and other intravascular inflammatory cells accumulate and migrate.…”

Urinary trypsin inhibitor attenuates the development of neuropathic pain following spinal nerve ligation

“…Ulinastatin, or urinary trypsin inhibitor (UTI), is a serine protease inhibitor [8] that can be used not only in inflammatory diseases such as pancreatitis or sepsis due to its anti-inflammatory effect but also in patients with shock, trauma, organ injury, or undergoing surgery due to its cytoprotective effects [8,9]. Moreover, ulinastatin is also effective in the protection of the nervous system after an injury [10,11].…”