Ulinastatin relieves sepsis-associated dysmotility via IL-1β-related enteric neuroprotection.

To analyze the clinical effect of ulinastatin (UTI)-somatostatin (SS) combination on acute severe pancreatitis (SAP) patients, focusing on changes in efficacy and serum inflammatory markers (IMs). This study retrospectively enrolled 104 SAP patients (July 2022-July 2025), with 51 patients (control group) treated with SS and 53 cases (observation group) receiving UTI+SS. Clinical efficacy, safety (rash, dizziness, diarrhea, nausea/vomiting, kidney injury, hyperglycemia), symptom relief time (vomiting, pyrexia, celialgia, defecation recovery, abdominal distension), disease-related indicators (blood amylase [AMS], Acute Physiology And Chronic Health Evaluation II [APACHE-II]), pancreatic function (insulin [INS], trypsinogen-2 [TPS2], glucose [Glu]), serum IMs (C-reactive protein [CRP], tumor necrosis factor [TNF]-α, interleukin [IL]-6), intestinal mucosal barrier function (diamine oxidase [DAO], D-lactic acid [D-Lac], endotoxin [ET]), laboratory-related indexes (total white blood cell count [WBC], platelet count [PLT], creatinine [Cr], total bilirubin [TBIL]), and humoral immunity (immunoglobulin [Ig] A/M/G) were comparatively assessed. Finally, determinants of patients' therapeutic effects were isolated by uni- and multivariate analyses. UTI+SS was markedly superior to sole SS in terms of overall effectiveness, INS, PLT, and IgA/M/G, along with faster symptom relief, lower AMS, APACHE-II scores, TPS2, Glu, CRP, TNF-α, IL-6, DAO, D-Lac, WBC, Cr, and TBIL. Total adverse reaction incidence showed no notable inter-group difference. CRP and Cr were independent risk factors for therapeutic efficacy among SAP patients, while treatment modality acted as an independent protective factor. UTI+SS for SAP is effective in clinical efficacy enhancement and serum inflammation suppression.

Neurodegenerative diseases are age-associated disorders characterized by distinctive pathological features. Microglia are essential for brain development and function. Modulating microglial activation in neurodegenerative diseases may provide novel therapeutic strategies. Ulinastatin (UTI), an intrinsic serine protease inhibitor, is widely used to treat acute inflammatory disorders. Although the anti-inflammatory effects of UTI have been studied, the mechanisms by which it affects microglial activation remain incompletely understood. In this study, we investigated the effects of UTI on lipopolysaccharide (LPS)-induced microglial activation in both rats and BV2 mouse microglial cells, with a focus on the MAPK and JAK-STAT signaling pathways. We employed Morris water maze, ELISA, MTT assay, immunohistochemistry, immunofluorescence, and western blotting to evaluate the impact of UTI. Our results showed that LPS induced microglial activation via MAPK and JAK-STAT signaling, resulting in elevated TNF-α and IL-1β expression and spatial learning deficits in rats. UTI treatment suppressed LPS-induced microglial activation by modulating these pathways, reduced pro-inflammatory cytokine production, and attenuated spatial memory impairment. Notably, our findings provide new evidence that UTI exerts anti-inflammatory and neuroprotective effects by targeting MAPK/JAK-STAT-mediated microglial activation, suggesting its potential as a therapeutic agent for neuroinflammatory and neurodegenerative diseases.

Inhibition of ferroptosis by serine protease inhibitor attenuates acute respiratory distress syndrome.

ObjectivesDeep hypothermic circulatory arrest (DHCA) is known to trigger a systemic inflammatory response and ischaemia-reperfusion injury, leading to exacerbated lung dysfunction. Ulinastatin (UTI) is a commonly used anti-inflammatory drug in clinical settings, but its protective effects may vary depending on the timing and dosage.MethodsA rat model of DHCA was established, and 2 different doses of UTI (5/10 × 104 U/kg; low/high dose) were administered. We measured the levels of inflammatory factors using enzyme-linked immunosorbent assay kits and assessed the functional indicators of lung tissue injury. All rats (n = 18) underwent the standard cardiopulmonary bypass (CPB) procedure with DHCA.ResultsFollowing rewarming, the levels of interleukin-6 (IL-6), IL-10, tumour necrosis factor (TNF)-α, and neutrophil elastase 2 (ELA-2) gradually increased in rats exposed to DHCA. Compared to the DHCA group, both the UTI groups exhibited significant reductions in IL-6 (DHCA vs DHCA+UTI-H, 8931.68 ± 650.31 vs 2498.05 ± 552.16), TNF-α (DHCA vs DHCA+UTI-H, 633.74 ± 74.53 vs 221.19 ± 31.63), and ELA-2 (DHCA vs DHCA+UTI-H, 4.94 ± 0.49 vs 3.29 ± 0.34), while remarkably increased the IL-10 (DHCA vs DHCA+UTI-H, 975.04 ± 110.33 vs 3081.27 ± 554.10) levels 4 hours after weaning from CPB (all P < 0.05). Interestingly, the high dose of UTI demonstrated a dose-dependent inhibition of inflammation. Meanwhile, we found that UTI contributed to maintain haemodynamic stability, improve tissue perfusion, and reduce hypoxia, as evidenced by elevated heart rate, blood pressure, haematocrit and oxygenation index, and decreased glucose and lactate. Reduced pathological changes in lung histopathology were also observed after UTI intervention, especially in 10 × 104 U/kg group.ConclusionsThis study revealed that administration of low to high doses of UTI during DHCA could reduce the release of inflammatory factors, exert anti-inflammatory effects, and alleviate lung injury.

BackgroundIntestinal barrier dysfunction plays a significant role in the development of pancreatic necrosis and multiple organ failure in AP. This study aimed to investigate the therapeutic effects and potential mechanisms of ulinastatin (UTI) on L-arginine-induced acute pancreatitis (AP)-associated intestinal barrier dysfunction in rats.MethodsExperimental rats were randomly divided into five subgroups as follows: control, AP, AP + UTI, AP + ML-385 and AP + UTI + ML-385. The pancreatic and intestinal injuries were assessed by enzyme-linked immunosorbent assay (ELISA), western blot, pathology, laser Doppler and transmission electron microscope (TEM). The inflammatory biomarkers were determined by western blot and the indicators of oxidative stress were also measured. The Nrf2 signaling pathway and macrophage polarization were evaluated by immunofluorescence staining, western blot and qRT–PCR analysis.ResultsUlinastatin treatment effectively improved both AP and AP-associated intestinal barrier dysfunction. Moreover, ulinastatin treatment significantly decreased the levels of pro-inflammatory factors and peroxides while significantly increasing the levels of anti-inflammatory factors and antioxidants. Mechanistically, ulinastatin treatment inhibited M1 macrophage polarization, achieved by activating the Nrf2 signaling pathway and facilitating Nrf2 nuclear translocation. The application of ML-385 to intercept Nrf2 eliminated ulinastatin-mediated suppression of macrophage M1 polarization and inflammation.ConclusionsUlinastatin protected against both AP and the associated intestinal barrier dysfunction. It suppressed the inflammatory response and oxidative stress by promoting Nrf2 nuclear translocation and inhibiting M1 macrophage polarization through the activation of the Nrf2 signaling pathway.

Radiotherapy-induced oral mucositis (RTOM) is a common side effect of radiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) receiving concurrent chemoradiotherapy (CCRT). In this phase 3 trial, we aim to evaluate the efficacy and safety of Ulinastatin (UTI) for the prevention and treatment of RTOM in LA-NPC patients (NCT03387774). The primary endpoint is the incidence of grade ≥3 acute RTOM during radiotherapy. Secondary endpoints include cumulative incidence of RTOM, recovery rate, the onset time and duration of grade ≥3 RTOM, oral pain (severe), safety and survival outcomes. 179 eligible patients are randomly assigned to UTI Group (n = 89) or Control group (n = 90). All UTI group patients complete UTI treatment as planned, and both groups complete scheduled CCRT. The incidence of grade 3 RTOM is significantly lower in UTI group compared with control group (25.8% vs 41.1%, P = 0.030). The trial meet its prespecified primary endpoint. No Ulinastatin related adverse events are observed during treatment. The 3-year overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) in UTI group and control group are similar between two groups. In this work, Ulinastatin can effectively reduce the severity of RTOM and oral pain without increasing toxicity and compromising survivals.

BackgroundDeep hypothermic circulatory arrest (DHCA) can cause systemic inflammatory response (SIR) and ischemia-reperfusion (I/R) injury, potentially exacerbating organ failure. Ulinastatin (UTI) is a frequently employed anti-inflammatory medication in clinical practice, but different timing and dosage may influence its protective efficacy.Methods24 rats were randomly divided into four groups. Three different doses of UTI (3/10/30 × 104 U/kg; low/medium/high dose) were administered in the DHCA rat model, with a control group that underwent DHCA without UTI administration. Inflammatory markers and routine clinical indicators of myocardial, hepatic, and renal tissue injury were evaluated. All rats underwent the standard DHCA procedure.ResultsInterleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and neutrophil elastase (ELA-2) levels in rats exposed to DHCA gradually increased after rewarming. Compared with the DHCA-only group, both the low dose of UTI (UTI-L) and the medium dose of UTI (UTI-M) significantly reduced IL-6 (p = 0.017, p = 0.022 ), TNF-α (p = 0.003, p < 0.001), ELA-2 levels ( p = 0.018, p = 0.001), and elevated IL-10 levels ( p < 0.001, p < 0.001) 4 h post-weaning from cardiopulmonary bypass (CPB). In addition, compared with the DHCA group, both the UTI-L and UTI-M group showed significantly lower levels of cardiac troponin I (p = 0.001, p = 0.001), creatine kinase muscle and brain isoenzyme (CK-MB) (p < 0.001, p < 0.001), creatinine (p < 0.001, p < 0.001), blood urea nitrogen (p = 0.002, p = 0.021), aspartate transaminase (p < 0.001, p < 0.001) and alanine aminotransferase (p < 0.001, p < 0.001) at the end of the experiment. The hematoxylin-eosin staining results of kidney and liver tissue damage were alleviated in the UTI-L and UTI-M groups. The high dose of UTI (UTI-H) group did not exhibit dose-dependent anti-inflammatory effects and was associated with aggravated injury to the heart, liver, and kidney.ConclusionThis study demonstrated that the administration of low to medium doses of UTI during DHCA significantly attenuated the levels of IL-6, TNF-α, and ELA-2, elevated the level of the anti-inflammatory factor IL-10, and provided protective effects on myocardial, hepatic, and renal tissues.

Severe sepsis is a systemic inflammatory response syndrome caused by infection, and the Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) scoring system is widely used to assess the severity of severe patients. Hybrid blood purification treatment (HBPT) and ulinastatin (UTI) have shown good efficacy in a variety of inflammatory diseases, and miR-146a and miR-155 were found to be closely related to inflammatory reaction. The purpose of this study was to investigate the effect of HBPT combined with UTI in the treatment of patients with severe sepsis, especially the effects on APACHE II score and miR-146a and miR-155 levels. We carried out a retrospective analysis of clinical data with severe sepsis admitted to our hospital from January 2020 to June 2022. The patients were divided into an HBPT or HBPT+UTI group according to the treatment records. The APACHE II score, miR-146a level, miR-155 level, inflammatory factors, and rehabilitation status of both groups were analyzed and compared before and after treatment. A total of 150 were included in the analysis, there were 77 participants in HBPT+UTI and 73 in HBPT group. After treatment, the APACHE II score and levels of miR-146a, miR-155, and inflammatory factors were significantly lower than that before treatment. Furthermore, the HBPT+UTI group showed significantly lower values than the HBPT group (all P < 0.05). The recovery time of serum amylase, the disappearance time of abdominal pain, and the length of hospitalization in the HBPT+UTI group were significantly shorter than those in the HBPT group (all P < 0.05). UTI treatment combined with the administration of HBPT could improve the APACHE II score, alleviate the inflammatory reaction, and significantly improve the short-term prognosis of the patients with severe sepsis.

This study aimed to assess the influence of ulinastatin (UTI) on lymphocyte apoptosis and autophagy in sepsis patients, as well as its effect on inflammatory factors and vital organ function, with the goal of providing insights for improved clinical management of sepsis. A total of 40 sepsis patients were randomly assigned to the UTI group or the control group. The UTI group received standard treatment plus intravenous UTI, while the control group received standard treatment alone. Peripheral blood samples were collected at multiple time points for analysis of lymphocyte apoptosis, autophagy, inflammatory markers, and organ function. Various experimental techniques including Hoechst staining, transmission electron microscopy, and Western blot analysis were utilized to assess lymphocyte apoptosis, autophagy, and related protein expression levels. The study revealed that UTI treatment significantly inhibited lymphocyte apoptosis and promoted autophagy in sepsis patients. The levels of autophagy-related proteins LC3-II and Beclin-1 were substantially elevated, while the ratio of anti-apoptotic Bcl-2 to pro-apoptotic Bax was increased following UTI treatment. Furthermore, the levels of inflammatory markers IL-6, procalcitonin, and C-reactive protein were markedly reduced in the UTI group compared to the control group. Additionally, UTI treatment led to improved liver, kidney and cardiac function as evidenced by reduced levels of liver enzymes and creatinine, and cardiac enzymes. The findings of this study demonstrate that UTI exerts a protective effect on septic patients by inhibiting lymphocyte apoptosis, promoting autophagy, and attenuating systemic inflammation. Moreover, UTI treatment was associated with improved liver, kidney, and cardiac function in septic patients. These results contribute to a better understanding of the clinical management of sepsis and underscore the potential of UTI as a therapeutic intervention in septic patients.

Renal fibrosis is a common outcome of chronic kidney diseases and glycolysis drives the development of renal fibrosis in damaged kidneys. Ulinastatin (UTI) is a broad-spectrum protease inhibitor with anti-inflammatory and antioxidant properties with anti-fibrosis effects. In this study, we aimed to verify whether UTI could exert anti-renal fibrosis effects by inhibiting glycolysis and explored the potential mechanisms. Renal fibrosis was induced in mice via unilateral ureteral obstruction (UUO). Transforming growth factor-β1 stimulates human kidney proximal tubular epithelial cells to undergo fibrotic changes. Histopathological staining was used to observe the pathological changes in the kidneys. The levels of fibrosis biomarkers, glycolytic enzymes, and key signaling molecules were determined using gene and protein assays. Cellular energy metabolism was measured using Seahorse XF24 analyzer. Modulated the activity of adenylate-activated protein kinase (AMPK) and hypoxia-inducible factor-1α (HIF-1α) to confirm that AMPK can regulate HIF-1α-mediated glycolysis. Furthermore, UTI and AMPK knockdown were combined to verify whether UTI could attenuate glycolysis via the AMPK pathway. UTI pretreatment improved UUO-induced renal injury and fibrosis. The expression of fibrosis biomarkers and glycolytic enzymes was reduced by UTI at both mRNA and protein levels. UTI treatment decreased the rate of glycolysis and the production of glycolytic intermediates in fibrotic cells and tissues. Furthermore, AMPK can regulate HIF-1α-mediated glycolysis in renal tubular epithelial cells. Finally, the attenuation of glycolysis by UTI was related to AMPK/HIF-1α pathway, and this effect was inhibited by knockdown AMPK. UTI can effectively alleviate renal fibrosis, which may be partly attributed to the reduction of glycolysis by regulating AMPK/HIF-1α pathway.

Abstract BACKGROUNDAn antifouling and acid/alkali‐resistant sulfonated polyethersulfone (S‐PES)/polysulfate (PSE) composite ultrafiltration (UF) membrane prepared via a nonsolvent‐induced phase separation (NIPS) method was used for the purification of ulinastatin (UTI) as an examplar protein‐based drug.RESULTThe effect of the content of S‐PES on the structure and UF performance of the S‐PES/PSE composite UF membrane was investigated. The acid/alkaline resistance of the S‐PES/PSE membranes was evaluated in the pH range 5–10 suitable for a UTI solution. UF desalination experiments were carried out on UTI elution collection solution, and the antifouling performance and long‐term stability of S‐PES/PSE composite UF membrane were evaluated. The results indicate that, for the optimal content of 4% S‐PES, pure water flux increased from 120 to 726 L m−2 h−1, WCA decreased from 79.3° to 51.0°, and the rejection of UTI was 95.90% ± 1.1% compared to PSE. Compared with PES and PSF membranes, the flux recovery rate of the S‐PES/PSE composite UF membrane was 80.63% (an increase of 32.48%), and the UTI adsorption was only 75.00 μg cm−2 (a decrease of 88.00%) after simulated antifouling experiments.CONCLUSIONThe S‐PES/PSE composite UF membrane has excellent long‐term stability, suggesting significant potential for application in the purification of protein‐based drugs and in large‐scale UTI purification. © 2024 Society of Chemical Industry (SCI).

Sepsis can induce sepsis-associated encephalopathy (SAE), with Ulinastatin (UTI) serving a critical anti-inflammatory role. This study aimed to identify the hub genes in an SAE mouse model following UTI intervention and investigate the underlying molecular mechanisms. Through differential expression analysis to obtain differentially expressed genes (DEGs), ie, UTI vs CLP (DEGs1) and Con vs CLP (DEGs2). After taking the intersection of the genes with opposite differential trends in these two parts and immune-related genes (IRGs), DE-IRGs were obtained. Hub genes in the protein-protein interaction (PPI) network were then determined using six algorithms from the Cytohubba plugin in Cytoscape. Gene set enrichment analysis (GSEA) was employed to explore the functional relevance of these hub genes. Additionally, the immune microenvironment across the three groups was compared, and hub gene-related drugs were predicted using an online database. Finally, qRT-PCR was used to validate the expression of the hub genes in hippocampal tissue from CLP mice. RNA sequencing obtained 864 differentially expressed genes (DEGs) (CLP vs Con) and 279 DEGs (UTI vs CLP). Taking the intersection of DEGs with opposite expression trends yielded 165 DEGs. Six key genes (ICAM - 1, IRF7, IL - 1β, CCL2, IL - 6 and SOCS3) were screened by six algorithms. Immune infiltration analysis found that Treg cells were reversed after treatment with UTI in the diseased state. A total of 106hub - gene - related drugs were predicted, among which BINDARIT - CCL2 and LIFITEGRAST - ICAM1 showed particularly high affinities. The qRT - PCR verification results were consistent with the sequencing results. In conclusion, ICAM-1, IRF7, IL-1β, CCL2, IL-6, and SOCS3 were identified as potential therapeutic targets in SAE mice treated with UTI. This study offers theoretical support for UTI as a treatment option for SAE.

Combining ulinastatin with TIENAM improves the outcome of sepsis induced by cecal ligation and puncture in mice by reducing inflammation and regulating immune responses

ObjectiveThis comparative analysis aimed to investigate the efficacy of Sivelestat Sodium Hydrate (SSH) combined with Ulinastatin (UTI) in the treatment of sepsis with acute respiratory distress syndrome (ARDS).MethodsA control group and an observation group were formed with eighty-four cases of patients with sepsis with ARDS, with 42 cases in each group. The control group was intravenously injected with UTI based on conventional treatment, and the observation group was injected with SSH based on the control group. Both groups were treated continuously for 7 days, and the treatment outcomes and efficacy of both groups were observed. The Murray Lung Injury Score (MLIS), Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) were compared. Changes in respiratory function, inflammatory factors, and oxidative stress indicators were assessed. The occurrence of adverse drug reactions was recorded.ResultsThe total effective rate in the observation group (95.24%) was higher than that in the control group (80.95%) (P < 0.05). The mechanical ventilation time, intensive care unit (ICU) hospitalization time, and duration of antimicrobial medication in the observation group were shorter and multiple organ dysfunction syndrome incidence was lower than those in the control group (P < 0.05). The mortality rate of patients in the observation group (35.71%) was lower than that in the control group (52.38%), but there was no statistically significant difference between the two groups (P > 0.05). MLIS, SOFA, and APACHE II scores in the observation group were lower than the control group (P < 0.05). After treatment, respiratory function, inflammation, and oxidative stress were improved in the observation group (P < 0.05). Adverse reactions were not significantly different between the two groups (P > 0.05).ConclusionThe combination of SSH plus UTI improves lung injury and pulmonary ventilation function, and reduces inflammation and oxidative stress in patients with sepsis and ARDS.

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 .

Ulcerative colitis is an inflammatory bowel disease with multiple pathogeneses. Here, we aimed to study the therapeutic role of ulinastatin (UTI), an anti-inflammatory bioagent, and its associated mechanisms in treating colitis. Dextran sulfate sodium was administrated to induce colitis in mice, and a subgroup of colitis mice was treated with UTI. The gut barrier defect and inflammatory manifestations of colitis were determined via histological and molecular experiments. In addition, transcriptomics, metagenomics, and metabolomics were employed to explore the possible mechanisms underlying the effects of UTI. We found that UTI significantly alleviated the inflammatory manifestations and intestinal barrier damage in the mice with colitis. Transcriptome sequencing revealed a correlation between the UTI treatment and JAK-STAT signaling pathway. UTI up-regulated the expression of SOCS1, which subsequently inhibited the phosphorylation of JAK2 and STAT3, thus limiting the action of inflammatory mediators. In addition, 16S rRNA sequencing illustrated that UTI maintained a more stable intestinal flora, protecting the gut from dysbiosis in colitis. Moreover, metabolomics analysis demonstrated that UTI indeed facilitated the production of some bile acids and short-chain fatty acids, which supported intestinal homeostasis. Our data provide evidence that UTI is effective in treating colitis and support the potential use of UTI treatment for patients with ulcerative colitis.

This retrospective cohort study aimed to evaluate the clinical efficacy of ulinastatin (UTI) and azithromycin (AZM) combination therapy in treating severe pneumonia in children and its impact on inflammatory cytokines and oxidative stress. This retrospective cohort study was conducted from January 1, 2019, to January 1, 2021, involving pediatric patients diagnosed with severe mycoplasma pneumonia (SMPP). The pediatric patients were divided into two groups: those receiving UTI and AZM combination therapy (treatment group) and those receiving azithromycin alone (control group). We compared the two groups regarding clinical data, disease outcomes, inflammatory cytokines, and oxidative stress levels. Baseline characteristics did not significantly differ between the two groups. UTI, in combination with AZM, significantly improved blood oxygen levels, inflammatory infection markers, and relevant clinical symptoms in patients with SMPP on the 3rd day of treatment. Additionally, it significantly reduced the levels of inflammatory cytokines TNF-a, IL-6, IL-1β, and IL-10, as well as oxidative stress markers GSH and SOD. Combining UTI and AZM can rapidly alleviate clinical symptoms and effectively control the progression of patients with SMPP. Therefore, this treatment approach deserves consideration for clinical promotion and utilization.

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.

Ferroptosis is a newly discovered form of cell death characterized by intracellular iron accumulation and subsequent lipid peroxidation, which has been identified in various pathological processes, such as acute kidney injury (AKI). Ulinastatin (UTI), known as an antioxidant and anti-inflammatory, has been reported to prevent kidney injury. Here, we investigated the protective effects of UTI on LPS-induced podocyte ferroptosis in vivo and in vitro. Conditionally immortalized mouse podocyte was exposed to LPS in the presence or absence of UTI in vitro for 48 h. The levels of reactive oxygen species (ROS) and intracellular Fe2+ were detected to value the effect of UTI treatment on the podocyte cell ferroptosis. We also evaluated the influence of UTI on kidney injury in vivo. LPS-induced mice were treated with vehicle or UTI at 50 U/g/d for 6 wk. We identified the important function of UTI in repressing ferroptosis and ameliorating podocyte injury. The treatment of UTI reduced accumulation of Fe2+ and lipid ROS in podocyte. The cell proliferation was induced by UTI compared with the LPS-treated group in vitro. UTI attenuated the podocyte cytoskeletal as well. Regarding the mechanism, we found that UTI upregulated solute carrier family 7 member 11 (SLC7A11) expression by reducing miR-144-3p in the cells. The overexpression of miR-144-3p blocked the protective role of UTI in podocyte ferroptosis. MiR-144-3p/SLC7A11 axis was involved in UTI-mediated podocyte cell proliferation in vitro. Furthermore, the treatment of UTI repressed podocyte injury and proteinuria in vivo, and the level of miR-144-3p was decreased while SLC7A11 expression was increased in comparison with the model mice. UTI prevents LPS-induced podocyte ferroptosis and subsequent renal dysfunction through miR-144-3p/SLC7A11 axis. These findings might provide a potential novel therapeutic option for AKI and other renal diseases affecting podocyte.