Ulinastatin Group Research Articles

Effectiveness of ulinastatin in critical care patients in real world: a retrospective multi-center study

ABSTRACT Objectives Ulinastatin has been applied in various diseases associated with inflammation, but its effectiveness lacks real-world evidence. We aimed to evaluate the effectiveness of ulinastatin based on a real-world database in the intensive care unit (ICU) patients. Methods This was a retrospective cohort study. ICU patient data from multi-centers in China were collected. Propensity score matching (PSM) was applied. The effectiveness of ulinastatin was evaluated by mortality, length of stay in the ICU and mechanical ventilation duration. Kaplan-Meier method was used to estimate the hazard ratio and plot the survival curve. Results A total of 2036 patients were analyzed after PSM. Mortality was significantly lower in the ulinastatin group than in the non-ulinastatin group (hazard ratio for death: 0.77; 95% confidence interval: 0.62–0.96; p = 0.018). Ulinastatin significantly reduced mortality at 28 days (10.0% vs. 13.6%), 60 days (13.9% vs. 18.2%) and 90 days (14.7% vs. 18.5%), length of stay in the ICU (median 8.0 d vs. 13.0 d), and mechanical ventilation duration (median 24.0 h vs. 25.0 h; p < 0.05). Conclusions Ulinastatin was beneficial for patients in the ICU, mainly by reducing mortality, length of ICU stay, and mechanical ventilation duration. This study provides evidence of the clinical effectiveness of ulinastatin.

The efficacy and safety of ulinastatin in the prevention and treatment of radiotherapy-induced oral mucositis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC): A multicenter, open-label, randomized controlled clinical trial.

6105 Background: Severe oral mucositis is a common radiation-induced toxicity in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemo-radiotherapy (CCRT). Ulinastatin (UTI) can reduce the inflammatory response by inhibiting the release of inflammatory factors, but its role in radiotherapy-induced oral mucositis (RTOM) is unclear. Therefore, we conducted a multicenter, open-label, randomized controlled clinical trial to investigate the efficacy and safety of UTI in the prevention and treatment of RTOM in LA-NPC patients. Methods: Patients with histologically confirmed LA-NPC who met the eligibility criteria were randomly assigned to UTI group and control group. All patients received radical intensity modulated radiation therapy (IMRT) and concurrent chemotherapy (cisplatin 100 mg/m2/3 weeks for 2 or 3 cycles). UTI of 100,000 units three times daily (5 days/week) was intravenously administrated from day 1 to the end of radiotherapy for UTI Group. The primary endpoint was the incidence of grade ≥ 3 acute RTOM during CCRT (Radiation Therapy Oncology Group, RTOG grading). The secondary endpoints included the cumulative incidence of RTOM, recovery rate (proportion of patients with grade ≥ 3 RTOM who recovered to grade ≤ 2 during CCRT), the onset time and duration of grade ≥ 3 RTOM, oral pain (Numerical rating scale, NRS), safety and survival outcomes. Results: From January, 2018, to December, 2021, 182 patients from 5 hospitals were enrolled. 179 patients were included for efficacy, safety and survival analysis (89 in the UTI group and 90 in the control group). All UTI group patients completed UTI treatment as planned, and both groups completed scheduled CCRT. The incidence of grade ≥ 3 RTOM was significantly lower in UTI group compared with control group (25.8% vs. 41.1%; P = 0.030). The recovery rate in UTI group was higher than that in control group (39.1% vs. 10.8%; P = 0.023). However, the onset time and the duration of grade ≥ 3 RTOM were similar between the two groups (Median [IQR] 26.00 [19.00, 33.00] days vs. 32.00 [20.50, 36.00] days; P= 0.621 and 12.00 [7.00, 18.00] days vs. 15.00 [8.00, 25.50] days; P= 0.209). The incidence of severe oral pain ( NRS score≥ 7 ) was significantly reduced in UTI group compared with the control group (22.5% vs. 36.7; P = 0.038). No UTI related adverse events were observed during treatment. With a median follow-up time of 41.6 months (IQR, 38.2 - 45.0 months), The 3-year OS, LRRFS, DMFS and PFS in UTI group and Control group were 96.5% vs. 94.3%, 91.2% vs. 87.2%, 95.2% vs. 92.1% and 89.9% vs. 85.1%, respectively (all P &gt; 0.05). Conclusions: Our study revealed that UTI can effectively reduce the incidence of graded ≥ 3 RTOM and severe oral pain without increasing adverse events and compromising survivals. Clinical trial information: NCT03387774 .

The Preventive Effect of Urinary Trypsin Inhibitor on Postoperative Cognitive Dysfunction, on the Aspect of Behavior, Evaluated by Y-Maze Test, via Modulation of Microglial Activity.

This experimental study was designed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor, on postoperative cognitive dysfunction (POCD) in rats under general anesthesia with isoflurane, on the aspect of behavior, as evaluated using a Y-maze test and focusing on microglial activity. Ulinastatin (50,000 U/mL) and normal saline (1 mL) were randomly (1:1) administered intraperitoneally to the ulinastatin and control groups, respectively, before general anesthesia. Anesthesia with isoflurane 1.5 volume% was maintained for 2 h. The Y-maze test was used to evaluate cognitive function. Neuronal damage using caspase-1 expression, the degree of inflammation through cytokine detection, and microglial activation with differentiation of the phenotypic expression were evaluated. Twelve rats were enrolled in the study and evenly allocated into the two groups, with no dropouts from the study. The Y-maze test showed similar results in the two groups before general anesthesia (63 ± 12% in the control group vs. 64 ± 12% in the ulinastatin group, p = 0.81). However, a significant difference was observed between the two groups after general anesthesia (17 ± 24% in the control group vs. 60 ± 12% in the ulinastatin group, p = 0.006). The ulinastatin group showed significantly lower expression of caspase-1. Pro-inflammatory cytokine levels were significantly lower in the ulinastatin group than in the control group. The ulinastatin group had a significantly lower microglial activation (41.74 ± 10.56% in the control group vs. 4.77 ± 0.56% in the ulinastatin, p < 0.001), with a significantly lower activation of M1 phenotypes (52.19 ± 7.83% in the control group vs. 5.58 ± 0.76% in the ulinastatin group, p < 0.001). Administering ulinastatin before general anesthesia prevented neuronal damage and cognitive decline after general anesthesia, in terms of the aspect of behavior, as evaluated by the Y-maze test. The protective effect of ulinastatin was associated with the inhibition of microglial activation, especially the M1 phenotype.

The effect of ulinastatin on acute kidney injury in patients undergoing off-pump cardiac bypass surgery

BackgroundUlinastatin, an anti-inflammatory and antioxidant trypsin inhibitor, has shown potential in mitigating acute kidney injury (AKI) and reducing serum creatinine levels after various surgeries. This retrospective study aimed to evaluate the effects of ulinastatin on AKI in patients undergoing off-pump coronary artery bypass (OPCAB) surgery.MethodsWe hypothesized that the administration of ulinastatin could prevent AKI in OPCAB. Electrical medical records were reviewed to identify OPCAB patients between January 2015 and June 2020. The utilization of ulinastatin was randomly determined and applied during this period. Acute kidney injury was defined according to the KDIGO guideline, and its incidence was compared between the ulinastatin administration group and the control group. To investigate the effect of ulinastatin on renal function, multivariate logistic regression analysis was used to calculate propensity scores for each group.ResultsA total 454 OPCAB were performed, and after following inclusion and exclusion process, 100 patients were identified in the ulinastatin group and 303 patients in the control group. Using 1:2 propensity score matching, we analyzed 100 and 200 patients in the ulinastatin and control groups. The incidence of AKI was similar between the groups (2.5% for the control group, 2.0% for the ulinastatin group, p > 0.999). However, the serum creatinine value on the first post-operative day were significantly lower in the ulinastatin group compared to the control group (0.774 ± 0.179 mg/dL vs 0.823 ± 0.216 mg/dL, P = 0.040), while no significant differences were observed for the other time points (P > 0.05). The length of ICU stay day was significantly shorter in the ulinastatin group (2.91 ± 2.81 day vs 5.22 ± 7.45 day, respectively, P < 0.001).ConclusionsUlinastatin did not have a significant effect on the incidence of AKI; it demonstrated the ability to reduce post-operative serum creatine levels at first post-operative day and shorten the length of ICU stay.

Effects of ulinastatin combined with dexmedetomidine on cognitive dysfunction and emergence agitation in elderly patients who underwent total hip arthroplasty.

With the continuous growth of the modern elderly population, the risk of fracture increases. Hip fracture is a common type of fracture in older people. Total hip arthroplasty (THA) has significant advantages in relieving chronic pain and promoting the recovery of hip joint function. To investigate the effect of ulinastatin combined with dexmedetomidine (Dex) on the incidences of postoperative cognitive dysfunction (POCD) and emergence agitation in elderly patients who underwent THA. A total of 397 patients who underwent THA from February 2019 to August 2022. We conducted a three-year retrospective cohort study in Shaanxi Provincial People's Hospital. Comprehensive demographic data were obtained from the electronic medical record system. We collected preoperative, intraoperative, and postoperative data. One hundred twenty-nine patients who were administered Dex during the operation were included in the Dex group. One hundred fifty patients who were intravenously injected with ulinastatin 15 min before anesthesia induction were included in the ulinastatin group. One hundred eighteen patients who were administered ulinastatin combined with Dex during the operation were included in the Dex + ulinastatin group. The patients' perioperative conditions, hemodynamic indexes, postoperative Mini-Mental State Examination (MMSE) scores, Ramsay score, incidence of POCD, and serum inflammatory cytokines were evaluated. There was a significant difference in the 24 h visual analogue scale score among the three groups, and the score in the Dex + ulinastatin group was the lowest (P < 0.05). Compared with the Dex and ulinastatin group, the MMSE scores of the Dex + ulinastatin group were significantly increased at 1 and 7 d after the operation (all P < 0.05). Compared with those in the Dex and ulinastatin groups, incidence of POCD, levels of serum inflammatory cytokines in the Dex + ulinastatin group were significantly decreased at 1 and 7 d after the operation (all P < 0.05). The observer's assessment of the alertness/sedation score and Ramsay score of the Dex + ulinastatin group were significantly different from those of the Dex and ulinastatin groups on the first day after the operation (all P < 0.05). Ulinastatin combined with Dex can prevent the occurrence of POCD and emergence agitation in elderly patients undergoing THA.

The impact of ulinastatin on wound infection and healing in patients with burn wounds: A meta-analysis.

Burn injuries result in localised tissue damage and precipitate systemic responses; routine clinical treatments, which typically include metabolic nutritional support and anti-infection therapies, do not yield optimal outcomes. Therefore, we aimed to systematically evaluate the effects of ulinastatin on wound infection and healing in patients with burns to provide reliable evidence-based recommendations for burn treatment. An electronic search of the Web of Science, PubMed, Cochrane Library, Embase, Wanfang, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure databases, supplemented by manual searches, was conducted from database inception to October 2023 to collect randomised controlled trials (RCTs) assessing the efficacy of ulinastatin for the treatment of burns. Two researchers screened all retrieved articles according to the inclusion and exclusion criteria; the included studies were evaluated for quality, and the relevant data were extracted. Stata 17.0 software was employed for data analysis. Overall, 8 RCTs with 803 patients were included, with 404 and 399 in the ulinastatin and conventional treatment groups, respectively. The analysis revealed that wound infections (odds ratio [OR] = 0.08, 95% CI: 0.02-0.35, p = 0.001) and complications (OR = 0.21, 95% CI: 0.10-0.42, p < 0.001) were significantly lower, and wound healing time (standardised mean differences [SMD] = -1.31, 95% CI: -2.05 to -0.57, p = 0.001) was significantly shorter, in the ulinastatin groups than in the control group. This meta-analysis revealed that ulinastatin can effectively reduce the incidence of wound infections and complications and significantly shorten the duration of wound healing in patients with burns, thereby promoting early recovery in these patients.

The role of TLR4/MyD88/NF-κB in the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis

ObjectiveTo investigate the effect of the TLR4/MyD88/NF-κB (Toll-like receptor 4/myeloid differentiation factor/nuclear factor kappa B) signalling pathway on the protective effect of ulinastatin on the intestinal mucosal barrier in mice with sepsis.MethodsA mouse model of sepsis was established by classical caecal ligation and perforation. Forty-four SPF C57BL/6 mice were randomly divided into the following four groups with 11 mice in each group: the control group (Con group), ulinastatin group (Uti group), Uti + LPS (lipopolysaccharide, LPS) group (Uti + LPS group) and LPS group. Mice in the Con group and Uti group received saline or ulinastatin injected 2 h after modelling; Mice in the Uti + LPS group received LPS injected 0 h after modelling, other procedures were the same as in the Uti group; Mice in the LPS group received LPS only. At 48 h after surgery, the levels of TNF-α (tumour necrosis factor-α, TNF-α), IL-6 (interleukin-6, IL-6) and IL-1β (interleukin-1β, IL-1β) in vein, and the expression of TLR4, MyD88 and NF-κB mRNA in small intestinal mucosa tissues using ELISA and RT‒PCR.ResultsThe pathological specimens showed increased inflammatory injury in the Con and LPS groups, while these injuries and changes improved in the Uti group. The scores of intestinal mucosal injury at 48 h of Uti injection were significantly lower than those of the Con group (P < 0.001), while the scores of intestinal mucosal injury of Uti + LPS were significantly higher than those of the Uti group (P = 0.044). The expression of TNF-α, IL-6 and IL-1β in the Uti decreased significantly at 48 h after surgery than that in the Con group (P = 0.001, P = 0.014, P = 0.004), while the expression of TNF-α, IL-6 and IL-1β in the Uti + LPS group increased significantly after surgery than that in the Uti group (P = 0.026, P = 0.040, P = 0.039). The expression of TLR4, MyD88 and NF-κB mRNA in the Uti group decreased significantly compared with that in the Con group (P = 0.001, P = 0.021, P = 0.007), while the expression of TLR4, MyD88 and NF-κB mRNA in the Uti + LPS group was higher than that in the Uti group (P = 0.023, P = 0.040, P = 0.045).ConclusionThese findings indicate that the protective effect of ulinastatin on the intestinal mucosal barrier against sepsis may be mediated through the TLR4/MyD88/NF-κB pathway.

Expression of Angiopoietin-2 in Lung Tissue of Juvenile SD Rats with Lipopolysaccharide-Induced Acute Lung Injury and the Role of Ulinastatin.

This study aimed to observe the expression of angiopoietin-2 (Ang-2) in the lung tissue of juvenile SD rats with lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to clarify the role of ulinastatin (UTI). Ninety 18-21-day-old juvenile SD male rats were randomly divided into five groups (n = 18). ALI rat model was established by intraperitoneal injection of LPS (LPS 10mg/kg), while the control group was given the same dose of normal saline. The UTI intervention group was given the injection of UTI (5000 U/mL) immediately after the injection of LPS, which was divided into UTI low-dose group (LPS + 5ml/kg UTI), UTI medium-dose group (LPS + 10ml/kg UTI), and UTI high-dose group (LPS + 20ml/kg UTI).The respiratory status of each group of rats was observed, and six rats were randomly selected to be killed in each group at 6, 12, and 24h, and the lung tissues were dissected and retained. The pathological changes of the lung tissues were observed by hematoxylin-eosin (HE) staining, the expression levels and locations of Ang-2 and vascular endothelial growth factor (VEGF) in lung tissue were observed by immunohistochemical staining, and the expressions of genes and proteins of Ang-2 and VEGF were detected by quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Three hours after intraperitoneal injection, rats in the model group developed shortness of breath and the developed respiratory distress progressed over time. The lung pathological changes in the model group were obvious compared with those in the control group, and gradually worsened with time, and the pathological changes of lung in the rats in the UTI intervention group were reduced compared with those in the model group. At different time points, the expressions of Ang-2 and VEGF in the lung tissue of rats in the model group were higher than those in the control group, and were lower in the UTI intervention group than those in the model group. The expressions of Ang-2 and VEGF protein were lower in the low-dose group of UTI group than those in the high-dose group of UTI group at different time points (P < 0.05), and the expressions of Ang-2 and VEGF protein in the low-dose group of UTI were significantly lower than those in the medium-dose group at 12h and 24h (P < 0.05). The expression of Ang-2 was increased in the lung tissue of juvenile SD rats with LPS-induced ALI, and was associated with the degree of lung injury. UTI might attenuate LPS-induced ALI by inhibiting the expression of Ang-2 in lung tissue, and the low dose was more obvious than the medium and high dose.

Combined Efficacy of Diosmin and Ulinastatin on Renal Injury Markers and Ultrasound Indicators in Delayed Renal Function Recovery

Renal transplantation, as an effective treatment for end-stage renal disease, has many clinical complications, among which delayed graft function recovery, as one of the common postoperative complications, is also a major risk factor affecting the short-term and long-term efficacy of renal transplantation. Therefore, reasonable use of delayed graft function after renal transplantation to promote renal function recovery is of great significance for the prognosis of these patients. Based on this, 62 patients who underwent renal transplantation and developed delayed graft function in our hospital from June 2017 to December 2019 were selected as the research objects. According to the random color method, they were divided into three groups; diosmin group (n=20), ulinastatin group (n=21) and combination group (n=21). To observe the effects of different medication regimens on renal injury markers and renal ultrasound related indexes in patients with delayed graft function and to lay a theoretical foundation for guiding clinical medication and improving prognosis of delayed graft function recovery patients. After comparing the general data of the three groups, it was found that there was no significant difference (p>0.05), indicating that there was no difference in medication results due to personal factors. The levels of serum creatinine, cystatin and blood urea nitrogen in the ulinastatin group after treatment were significantly better than those before treatment. The levels of renal injury markers in the combined group were significantly better after treatment than before treatment. According to the ultrasound results, there was no significant difference in the renal ultrasound indexes between the diosmin and ulinastatin groups after treatment, while the renal ultrasound indexes of the combined group were better than those of the other two groups. It can be concluded from the results that diosmin combined with ulinastatin can significantly reduce renal injury in patients with delayed graft function and can effectively improve renal function in such patients, which has a positive effect on improving prognosis.

Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass: A Prospective Cohort Study with 10-Year Follow-Up

Introduction: The present study aimed to explore the potential effect of ulinastatin on renal function and long-term survival in patients receiving cardiac surgery with cardiopulmonary bypass (CPB). Methods: This prospective cohort study was conducted at Fuwai Hospital, Beijing, China. Ulinastatin was applied after induction anesthesia. The primary outcome was the rate of new-onset postoperative acute kidney injury (AKI). Moreover, a 10-year follow-up was conducted until January 2021. Results: The rate of new-onset AKI was significantly lower in the ulinastatin group than in the control group (20.00 vs. 32.40%, p = 0.009). There was no significant difference in renal replacement therapy between the two groups (0.00 vs. 2.16%, p = 0.09). The postoperative plasma neutrophil gelatinase-associated lipocalin (pNGAL) and IL-6 levels were significantly lower in the ulinastatin group compared with the control group (pNGAL: p = 0.007; IL-6: p = 0.001). A significantly lower incidence of respiratory failure in the ulinastatin group compared with the control group (0.76 vs. 5.40%, p = 0.02). The nearly 10-year follow-up (median: 9.37, 95% confidence interval: 9.17–9.57) survival rates did not differ significantly between the two groups (p = 0.076). Conclusions: Ulinastatin significantly reduced postoperative AKI and respiratory failure in patients receiving cardiac surgery with CPB. However, ulinastatin did not reduce intensive care unit and hospital stays, mortality, and long-term survival rate.

High-dose ulinastatin reduces postoperative bleeding and provides platelet-protective effects in patients undergoing heart valve replacement surgery

The aim of this prospective study was to investigate the effect of a high dose of ulinastatin on platelets and coagulation in patients undergoing mitral valve and/or aortic valve replacement with cardiopulmonary bypass (CPB). 273 patients were enrolled in this open-label study. According to patients' willingness, 243 patients were assigned to the ulinastatin group and 30 to the control group. In the ulinastatin group, ulinastatin (300,000 U) was given after the induction of anesthesia, ulinastatin (400,000 U) was added to the CPB pump prime, and then ulinastatin (300,000 U) was administered after weaning from CPB. Complete blood count and coagulation function test were conducted 1 day before surgery and on the first postoperative day. Bleeding and other safety events were recorded during hospitalization. Less postoperative major bleeding occurred in the ulinastatin group (0.4 vs. 6.7%, p=0.03). Moreover, 1 day after CPB, platelet count in the ulinastatin group increased significantly compared to that in the control group (157.7±71.0 vs. 132.1±59.6, p=0.03). Interestingly and contrary to what was expected, activated partial thromboplastin time (APTT) and prothrombin time (PT) did not differ significantly between the two groups. Ulinastatin application did not cause significant increase in total costs (p=0.89). In heart valve replacement surgery with CPB, high-dose ulinastatin could reduce postoperative bleeding and promote platelet recovery with no significant additional medical cost.

Taraxasterol Inhibits Hyperactivation of Macrophages to Alleviate the Sepsis-induced Inflammatory Response of ARDS Rats.

To explore the effect and mechanism of taraxasterol on sepsis-induced acute respiratory distress syndrome (ARDS). Twenty-four male SD rats were randomly divided into four groups: the control group, model (lipopolysaccharide, LPS) group, lipopolysaccharide+taraxasterol (LPS + TXL) group, and lipopolysaccharide+ulinastatin (LPS + UTI) group. The model of sepsis-induced ARDS was established by intraperitoneal injection of LPS. The lung water content of the rats in each group was determined by the dry/wet ratio. Pathology of rat lung tissue was observed through H&E staining. Wright staining was applied to count the number of neutrophils, macrophages, and total cells. ELISA was utilized to measure the levels of the inflammatory factors TNF-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid (BALF). Biochemical detection was adopted to check the levels of myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) in lung tissue. Western blotting was performed to check the protein expression of IL-12, iNOS, Arg-1, and Mrc1 in lung tissue. Compared with the LPS group, both taraxasterol and ulinastatin significantly decreased lung tissue water content, improved lung tissue injury, reduced the number of neutrophils, macrophages and total cells, and decreased the level of inflammatory factors. In addition, taraxasterol and ulinastatin also reduced the content of MPO and the expression of IL-12 and iNOS and increased the activity of SOD and CAT as well as the protein expression of Arg-1 and Mrc1. Taraxasterol can suppress macrophage M1 polarization to alleviate the inflammatory response and oxidative stress, thereby treating sepsis-induced ARDS.

Protective Effect of Ulinastatin on Cognitive Function After Hypoxia.

Ulinastatin (UTI) has neuroprotective properties. Neurologic insults, including hypoxia and use of anesthetic agents, cause postoperative cognitive dysfunction and alter gamma-aminobutyric acid (GABA) function. This study aimed to assess whether UTI could preserve learning and memory using a zebrafish hypoxic behavior model and biomarkers. Zebrafish (6-8months of age and 2.5-3.5cm long) were divided into eight groups as follows: phosphate-buffered saline (PBS) control, hypoxia + PBS, UTI (10,000, 50,000, and 100,000 units/kg), and hypoxia with UTI (10,000, 50,000, and 100,000 units/kg) groups. The endpoints of the T-maze experiment included total time, distance moved, and frequency in target or opposite compartment. We also measured the degree of brain infarction using 2,3,5‑triphenyltetrazolium chloride staining, assessed SA-β-galactosidase activity, and examined GABAA receptor expression using real-time polymerase chain reaction. In a dose-dependent manner, UTI affected learning and memory in zebrafish. Despite hypoxia, 100,000 units/kg of UTI preserved preference (time and distance) for the target compartment. More than 50,000 units/kg of UTI also showed reduced hypoxia-induced brain infarction, decreased SA-β-galactosidase levels, and upregulated GABAA receptors. This study demonstrated that the location of the GABAA receptor is affected by hypoxia or UTI.

Analysis of transcriptome characteristics of UTI therapy for cerebral injury after CA/ROSC based on RNA-seq technique.

Objective(s):To study the effects and mechanisms of ulinastatin (UTI) on brain injury caused by cardiac arrest/return of spontaneous circulation (CA/ROSC). Materials and Methods:In this study, modeling of CA/ROSC was set up in 56 Sprague Dawley (SD) rats, which were randomly divided into the model group, UTI (100000U/kg) treatment group, and control group. Each group then was divided into two subgroups: 24 hr and 72 hr. The survival rates between different groups was observed during two weeks. AimPlex multiplex immunoassays technology was performed to detect the expression of inflammatory cytokines in serum, such as IL-6 and TNF-α. RNA-sequencing (RNA-seq) transcriptome, Gene Ontology (GO), and Kyoto. Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to investigate the possible mechanism of UTI. Western blot and immunohistochemistry were performed to detect the expression of C-C motif chemokine ligand 2 (CCl2) and plasminogen (plg) protein expression.Results:The survival rate of the UTI group was significantly higher than the model group during two weeks. And UTI can significantly reduce the content of IL-6 and TNF-α in serum. GO and KEGG pathway enrichment analysis revealed that differentially expressed genes mainly belonged to the IL-17 signaling pathway and neuroactive ligand-receptor interaction signaling pathway. Besides, UTI can down-regulate the expression of the CCl2 inflammatory gene and up-regulate the expression of plg in the brain tissue of CA/ROSC rats. Conclusion:UTI has neuroprotective effects on brain injury after CA/ROSC. And the key mechanisms belong to the regulation of immune-inflammatory response as well as the signaling molecules and interaction.

Integrated Single Cell and Bulk RNA-Seq Analysis Revealed Immunomodulatory Effects of Ulinastatin in Sepsis: A Multicenter Cohort Study.

Sepsis is a leading cause of morbidity and mortality in the intensive care unit, which is caused by unregulated inflammatory response leading to organ injuries. Ulinastatin (UTI), an immunomodulatory agent, is widely used in clinical practice and is associated with improved outcomes in sepsis. But its underlying mechanisms are largely unknown. Our study integrated bulk and single cell RNA-seq data to systematically explore the potential mechanisms of the effects of UTI in sepsis. After adjusting for potential confounders in the negative binomial regression model, there were more genes being downregulated than being upregulated in the UTI group. These down-regulated genes were enriched in the neutrophil involved immunity such as neutrophil activation and degranulation, indicating the immunomodulatory effects of UTI is mediated via regulation of neutrophil activity. By deconvoluting the bulk RNA-seq samples to obtain fractions of cell types, the Myeloid-derived suppressor cells (MDSC) were significantly expanded in the UTI treated samples. Further cell-cell communication analysis revealed some signaling pathways such as ANEEXIN, GRN and RESISTIN that might be involved in the immunomodulatory effects of UTI. The study provides a comprehensive reference map of transcriptional states of sepsis treated with UTI, as well as a general framework for studying UTI-related mechanisms.

Effects of Fasting and Administration of Octreotide Acetate and Ulinastatin on Clinical Outcomes of Pancreatic Fistula After Pancreatoduodenectomy

Objective Postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy is the most serious complication of these surgical procedures; therefore, we examined the effectiveness of fasting, and administration of octreotide acetate and ulinastatin as a method of prevention. Summary of Background Data Although various drug therapies and surgical techniques have been used for the treatment of POPF, no decisive treatment for POPF exists. Methods The clinical course of 30 patients who developed POPF was retrospectively evaluated and compared among no dietary intake (n = 18), octreotide acetate (n = 8), and ulinastatin (n = 8) using an overlapping design. Patients were allocated to either the dietary intake or fasting (no dietary intake) group, and those in the no dietary intake group were further divided into the octreotide acetate or ulinastatin group. Results Length of hospitalization was longer for the no dietary intake group than for the dietary intake group (P = 0.002). When considering only grade B or C POPF cases, the no dietary intake group had a longer length of hospitalization and a higher white blood cell count on day 7 after the diagnosis of POPF than the dietary intake group (P &amp;lt; 0.05). The white blood cell count was also higher in the octreotide acetate group than in the ulinastatin group (P = 0.021). The length of hospitalization was shorter in the ulinastatin group than in the octreotide acetate group (P = 0.025). Conclusions The use of no dietary intake, octreotide acetate, and ulinastatin does not seem to contribute to the clinical course of patients with POPF after pancreatoduodenectomy.

Effect of ulinastatin on the inflammatory response after video-assisted thoracic lobectomy in patients with lung cancer: a randomized controlled study.

Background:The first-line treatment for lung cancer is surgical resection, and one-lung ventilation (OLV) is the most basic anesthetic management method in lung surgery. During OLV, inflammatory cytokines are released in response to the lung tissue damage and promote local and contralateral lung damage through the systemic circulation. We designed a randomized, prospective study to evaluate the effect of the urinary trypsin inhibitor (UTI) ulinastatin on the inflammatory response after video-assisted thoracic lobectomy in patients with lung cancer.Methods:Adult patients aged 19 to 70 years, who were scheduled for video-assisted thoracic lobectomy surgery to treat lung cancer between May 2020 and August 2020, were enrolled in this randomized, prospective study. UTI (300,000 units) mixed with 100 mL of normal saline in the ulinastatin group and 100 mL of normal saline in the control group was administered over 1 h after inducing anesthesia.Results:The baseline (T0) interferon-γ (IFN-γ)/interleukin-4 (IL-4) ratio was not different between the groups (6941.3 ± 2778.7 vs. 6954.3 ± 2752.4 pg/mL, respectively; P > 0.05). The IFN-γ/IL-4 ratio was significantly higher in ulinastatin group at 30 min after entering the recovery room than control group (20,148.2 ± 5054.3 vs. 6674.0 ± 2963.6, respectively; adjusted P < 0.017).Conclusion:Administering UTI attenuated the anti-inflammatory response, in terms of INF-γ expression and the IFN-γ/IL-4 ratio, after video-assisted thoracic surgery in lung cancer patients.Trial registration:Clinical Research Information Service of Korea National Institute of Health (CRIS), KCT0005533.

Ulinastatin Improves Renal Microcirculation by Protecting Endothelial Cells and Inhibiting Autophagy in a Septic Rat Model

Introduction: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. Methods: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 h after the operation. Histological staining was used to evaluate kidney injury scores. Western blot was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors (interleukin-1β, interleukin-6, and tumor necrosis factor-α) in kidney tissue, and enzyme-linked immunosorbent assay detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. Results: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. Conclusion: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Retrospective analysis of the role of Ulinastatin in reducing mortality in severe pancreatitis in critical care unit in Nepal

Background: Acute pancreatitis sequelae require a multidisciplinary approach and ICU care. Ulinastatin is a serine proteases inhibitor that reduces inflammation by suppressing the infiltration of neutrophils and elastase release and inflammatory mediators that help improve clinical symptoms and reduce mortality. This study aims to evaluate the clinical utility of Ulinastatin. Methods: Fifty-two patients admitted to ICU with acute pancreatitis were divided into; Ulinastatin group who received a 3 to 5 days course of 200,000IU, and Control Group who didn’t receive ulinastatin. Pearson's Chi-square and Fisher's exact test were used and a p-value &lt; 0.05 was considered statistically significant. Results: Mean age was lower among the Ulinastatin group at 43 years (p-Value 0.014) and Hepatic dysfunction was more among this group (p-value 0.04). Among new onset of organ dysfunction, only CVS dysfunction was significant among the Control group ( p-value 0.044) while respiratory function recovery (p-value 0.04) and coagulation profile improvement (p-value 0.017) was statistically significant among the Ulinastatin group. The mean duration of hospital stay was shorter among control group, 9.65 days vs 14 days, a p-value of 0.05and also the average duration of stay in MDICU was lower, 4 days vs 8.5 days, p-value 0.0044 in comparison to Ulinastatin group. Overall mortality incidence was 15.38%, 19% in Ulinastatin group vs 11.5% in Control group. Conclusion: This retrospective study is our experience in the use of Ulinastatin which has shown little efficacy in declining mortality and/or hospital stay duration though it helps prevent new organ dysfunctions.

Sigma-1 Receptor and Binding Immunoglobulin Protein Interact with Ulinastatin Contributing to a Protective Effect in Rat Cerebral Ischemia/Reperfusion

To investigate impact of ulinastatin (UTI) on sigma-1 receptor (σ1R) and binding immunoglobulin protein (BiP) after cerebral ischemia/reperfusion injury. The middle cerebral artery occlusion (MCAO) model was used to induce cerebral ischemia/reperfusion injury. Eighty male Sprague Dawley rats were randomly divided into 6 groups: control, MCAO, MCAO+50,000 U/kg UTI, MCAO+100,000 U/kg UTI, MCAO+200,000 U/kg UTI, MCAO+300,000 U/kg UTI. At 24 and 48 hours after MCAO, infarct volume, neurological dysfunction, and grip strength test were measured, and level of σ1R and BiP proteins was further detected using Western blot. Molecular docking assays were carried out to verify interaction between σ1R, BiP, and UTI. The serum concentration of BiP and the binding assay between σ1R, BiP, and UTI were determined using enzyme-linked immunosorbent assay. UTI increased the modified neurological severity score and upregulated σ1R and BiP expression in the cerebral cortex after MCAO. The grip strength of forelimbs increased significantly in the MCAO+200,000 U/kg UTI and MCAO+300,000 U/kg UTI groups compared with the MCAO group, while BiP serum levels remained unchanged. The molecular docking assay indicated putative binding between σ1R, BiP, and UTI. The binding assay also revealed that both σ1R and BiP could be combined with UTI. UTI displays a neuroprotective effect via upregulation of σ1R and BiP during ischemia/reperfusion injury, suggesting that UTI modulates σ1R and BiP and their interaction may provide a novel insight into potential therapeutic mechanisms for stroke.