COVID-19 is known for its magical infectivity, fast transmission and high death toll based on the large number of infected people. From the perspective of the clinical manifestation, autopsy examination and pathophysiology, the essence of COVID-19 should be viewed as a sepsis induced by viral infection, and has the essential characteristics as sepsis induced by other pathogens. Therefore, in addition to etiological and supportive treatment, immunomodulatory therapy is also appropriate to severe COVID-19. Although there is still a lack of consensus on immunotherapy for sepsis so far, relatively rich experiences have been accumulated in the past decades, which will help us in the treatment of severe COVID-19. This article will elaborate immunotherapy of sepsis, though it may not be consistent.
Adrenal Cortex Hormones ; therapeutic use ; Betacoronavirus ; Coronavirus Infections ; complications ; Glycoproteins ; therapeutic use ; Humans ; Immunologic Factors ; therapeutic use ; Pandemics ; Pneumonia, Viral ; complications ; Sepsis ; drug therapy ; etiology ; Thymalfasin ; therapeutic use

Adenoviridae ; genetics ; Ebolavirus ; genetics ; pathogenicity ; Gene Transfer Techniques ; Genetic Vectors ; therapeutic use ; Glycoproteins ; genetics ; HEK293 Cells ; Hemorrhagic Fever, Ebola ; genetics ; pathology ; virology ; Humans ; Inflammation ; genetics ; pathology ; virology ; Mucins ; genetics ; Transfection ; Viral Envelope Proteins ; genetics

OBJECTIVETo investigate the effect of ulinastatin (UTI) for early drug intervention on the serum levels of tumor necrosis factor-α (TNF-α), P-selectin, and thrombin-antithrombin complex (TAT) in young rats with sepsis.

METHODSA total of 120 male rats aged 4 weeks were randomly divided into normal control group, sham-operation group, sepsis group, low-dose UTI group (50 000 U/kg), and high-dose UTI group (200 000 U/kg), with 24 rats in each group. Modified cecal ligation and puncture was performed to establish a rat model of sepsis, and the rats in the low- and high-dose UTI groups were given caudal vein injection of UTI after model establishment. ELISA was used to measure the serum levels of TNF-α, P-selectin, and TAT at 6, 12, and 24 hours after model establishment.

RESULTSThe sepsis group had significant increases in the serum levels of TNF-α, P-selectin, and TAT at 6 hours, and the serum levels of TNF-α and TAT continued to increase by 24 hours (P<0.05); P-selectin reached the peak at 12 hours and decreased slightly at 24 hours (P<0.05). The UTI groups had similar change patterns in the levels of P-selectin and TAT as the sepsis group. The UTI groups had significant increases in the level of TNF-α at 6 hours, but gradually decreased over time. The changes in serum levels of TNF-α, P-selectin, and TAT in the UTI groups were significantly smaller than in the sepsis group (P<0.05). The high-dose UTI group had significantly smaller changes in serum levels of TNF-α, P-selectin, and TAT than the low-dose UTI group (P<0.05).

CONCLUSIONSEarly intervention with UTI can significantly improve coagulation function and inhibit the production of TNF-α, P-selectin, and TAT in young rats with sepsis. High-dose UTI has a significantly greater effect than low-dose UTI.

Animals ; Antithrombin III ; Glycoproteins ; pharmacology ; therapeutic use ; Male ; P-Selectin ; blood ; Peptide Hydrolases ; blood ; Rats ; Rats, Sprague-Dawley ; Sepsis ; blood ; drug therapy ; Tumor Necrosis Factor-alpha ; blood

BACKGROUNDIn addition to neurons, all components of the neurovascular unit (NVU), such as glial, endothelial, and basal membranes, are destroyed during traumatic brain injury (TBI). Previous studies have shown that excessive stimulation of calpain is crucial for cerebral injury after traumatic insult. The objective of this study was to investigate whether calpain activation participated in NVU disruption and edema formation in a mouse model of controlled cortical impact (CCI).

METHODSOne hundred and eight mice were divided into three groups: the sham group, the control group, and the MDL28170 group. MDL28170 (20 mg/kg), an efficient calpain inhibitor, was administered intraperitoneally at 5 min, 3 h, and 6 h after experimental CCI. We then measured neurobehavioral deficits, calpain activity, inflammatory mediator levels, blood-brain barrier (BBB) disruption, and NVU deficits using electron microscopy and histopathological analysis at 6 h and 24 h after CCI.

RESULTSThe MDL28170 treatment significantly reduced the extent of both cerebral contusion (MDL28170 vs. vehicle group, 16.90 ± 1.01 mm΃ and 17.20 ± 1.17 mm΃ vs. 9.30 ± 1.05 mm΃ and 9.90 ± 1.17 mm΃, both P < 0.001) and edema (MDL28170 vs. vehicle group, 80.76 ± 1.25% and 82.00 ± 1.84% vs. 82.55 ± 1.32% and 83.64 ± 1.25%, both P < 0.05), improved neurological scores (MDL28170 vs. vehicle group, 7.50 ± 0.45 and 6.33 ± 0.38 vs. 12.33 ± 0.48 and 11.67 ± 0.48, both P < 0.001), and attenuated NVU damage resulting (including tight junction (TJ), basement membrane, BBB, and neuron) from CCI at 6 h and 24 h. Moreover, MDL28170 markedly downregulated nuclear factor-κB-related inflammation (tumor necrosis factor-α [TNF-α]: MDL28170 vs. vehicle group, 1.15 ± 0.07 and 1.62 ± 0.08 vs. 1.59 ± 0.10 and 2.18 ± 0.10, both P < 0.001; inducible nitric oxide synthase: MDL28170 vs. vehicle group, 4.51 ± 0.23 vs. 6.23 ± 0.12, P < 0.001 at 24 h; intracellular adhesion molecule-1: MDL28170 vs. vehicle group, 1.45 ± 0.13 vs. 1.70 ± 0.12, P < 0.01 at 24 h) and lessened both myeloperoxidase activity (MDL28170 vs. vehicle group, 0.016 ± 0.001 and 0.016 ± 0.001 vs. 0.024 ± 0.001 and 0.023 ± 0.001, P < 0.001 and 0.01, respectively) and matrix metalloproteinase-9 (MMP-9) levels (MDL28170 vs. vehicle group, 0.87 ± 0.13 and 1.10 ± 0.10 vs. 1.17 ± 0.13 and 1.25 ± 0.12, P < 0.001 and 0.05, respectively) at 6 h and 24 h after CCI.

CONCLUSIONSThese findings demonstrate that MDL28170 can protect the structure of the NVU by inhibiting the inflammatory cascade, reducing the expression of MMP-9, and supporting the integrity of TJ during acute TBI.

Animals ; Brain Injuries, Traumatic ; drug therapy ; metabolism ; Calpain ; antagonists & inhibitors ; metabolism ; Dipeptides ; therapeutic use ; Disease Models, Animal ; Glycoproteins ; therapeutic use ; Inflammation ; drug therapy ; metabolism ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Mice ; Mice, Inbred BALB C ; NF-kappa B ; metabolism ; Peroxidase ; antagonists & inhibitors ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo investigate the protective effects of high-dose ulinastatin on the vital organs in patients undergoing total arch replacement for type A aortic dissection.

METHODSBetween September 2014 and March 2016, 66 patients with type A aortic dissection underwent total arch replacement at our center. Thirty-six of the patients received ulinastatin treatment at 300 000 U/8 h from admission to 3 days postoperatively and at 300 000 U/2 h during cardiopulmonary bypass surgery (UTI group), and the other 30 patients did not receive perioperative ulinastatin treatment (control group). The surgical data and blood biochemistry profiles on days 1, 3, and 5 postoperatively were compared between the two groups, and the postoperative ICU stay, re-operation for bleeding, ventilation for over 7 days, ultrafiltration for postoperative renal failure, tracheotomy, incidences of pulmonary and neurological complications and hospital death were also compared.

RESULTSs The operating time, cardiopulmonary bypass time, ACP time, cardiac arrest time, the lowest rectal temperature and frequency of bilateral and unilateral antegrade selective cerebral perfusion were similar between the two groups (P>0.05). Compared with those in the control group, patients in UTI group had lower lactate, S-100 and neuron specific enolase levels on the first postoperative day and higher OI on the 1st, 3rd, and 5th postoperative days (P<0.05), but serum creatinine, blood urea nitrogen, total bilirubin, and alanine aminotransferase levels were comparable between the two groups (P>0.05). No significant differences were found in the frequency of re-operation for bleeding, ultrafiltration for renal failure, tracheotomy, neurological complications or hospital death after the operation between the two groups, but the patients in UTI group had a shorter ICU time, a less frequent long-term ventilation and a lower incidence of pulmonary infection (P<0.05).

CONCLUSIONHigh-dose ulinastatin offers protection on pulmonary function and lowers the specific brain injury markers in patients with type A aortic dissection after total arch replacement, but its protective effects on brain is uncertain.

Aneurysm, Dissecting ; surgery ; Aorta, Thoracic ; surgery ; Aortic Aneurysm, Thoracic ; surgery ; Body Temperature ; Brain ; drug effects ; Cardiopulmonary Bypass ; Cerebrovascular Circulation ; Glycoproteins ; therapeutic use ; Humans ; Incidence ; Lactic Acid ; blood ; Lung ; drug effects ; Perfusion ; Phosphopyruvate Hydratase ; blood ; Postoperative Period ; Protective Agents ; therapeutic use ; S100 Proteins ; blood ; Time Factors

OBJECTIVETo observe the effect of sodium bicarbonate combined with ulinastatin on cholinesterase activity for patients with acute phoxim pesticide poisoning.

METHODSA total of 67 eligible patients with acute phoxim pesticide poisoning, Who were admitted to the emeryency department of hospital from March 2011 to February 2014, Acording to different treatments au patients were randomly divided into the conventional treatment group (n=34) and the sodium bicarbonate+ulinastatin group (n=35) . The conventional treatment group were given thorough gastric lavage with water, the sodium bicarbonate + ulinastatin group were given gastric lavage with 2% sodium bicarbonate solution. Both groups were given such treatments as catharsis, administration of oxygen, fluid infusion, diuresis, and antidotes such as atropine and pralidoxime methylchloride. On the basis of comprehensive treatment, people in the sodium bicarbonate+ulinastatin group were given 5% sodium bicarbonate injection and ulinastatin. The clinical effect of the two groups were compared.

RESULTSThe serum cholinesterase activity of the sodium bicarbonate+ulinastatin group was significantly higher than the conventional treatment group from the 5th day, and the difference was statistically significant (P<0.05) . The total atropine dosage, total pralidoxime methylchloride dosage and hospitalization days were better than the conventional treatment group, and the differences were statistically significant (P<0.05) . The difference in the time of atropinization between the two groups was not statistically significant (P>0.05) . The results of arterial blood pH, HCO3- of the sodium bicarbonate + ulinastatin group were higher than the conventional treatment group, and the difference of HCO3- at the 10th day was statistically significant (P<0.05) .

CONCLUSIONSSodium bicarbonate combined with ulinastatin can improve the therapeutic effect and reduce complications in the treatment of acute phoxim pesticide poisoning, and have beneficial effects on the recovery of cholinesterase activity.

Atropine ; therapeutic use ; Cholinesterases ; metabolism ; Glycoproteins ; therapeutic use ; Humans ; Organophosphate Poisoning ; drug therapy ; Organothiophosphorus Compounds ; poisoning ; Pesticides ; poisoning ; Pralidoxime Compounds ; therapeutic use ; Sodium Bicarbonate ; therapeutic use

OBJECTIVETo primarily evaluate the effects of ulinastatin on immune function of patients with severe burn injury.

METHODSForty patients with severe burn admitted to our ward from March 2013 to October 2015, conforming to the study criteria, were divided into conventional treatment group (CT, n=20) and ulinastatin treatment group (UT, n=20) according to the random number table and patient's consent. After admission, patients in group CT received antishock treatment, antibiotic treatment, debridement, skin grafting, and nutrition support, etc. On the basis of the above-mentioned treatment, patients in group UT received intravenous drip of ulinastatin from first day after admission twice a day, with a dosage of 8×10(5) U every time, for 7 days in addition. Peripheral venous blood samples were collected from patients in groups CT and UT on post treatment day (PTD) 1, 3, 5 and 7, respectively. Twenty healthy volunteer were selected as health control group (HC), and peripheral venous blood samples were collected on the first day of the study. Percentage of CD4(+) CD25(+) regulatory T lymphocytes (Tregs) was determined by flow cytometer. The proliferative activity of T lymphocytes was detected by microplate reader (denoted as absorbance value). Content of interleukin 2 (IL-2) in culture supernatant of T lymphocytes, and content of IL-4 and γ interferon (IFN-γ) in serum were detected by enzyme-linked immunosorbent assay. Expression of human leukocyte antigen-DR (HLA-DR) on CD14(+) monocytes was determined by flow cytometer. Data were processed with analysis of variance for repeated measurement, chi-square test, and LSD-t test.

RESULTS(1) Compared with that of volunteer in group HC, the percentage of CD4(+) CD25(+) Tregs of patients in group CT was significantly increased from PTD 1 to 7 (with t values from 13.303 to 26.043, P values below 0.01). Compared with that in group CT, the percentage of CD4(+) CD25(+) Tregs of patients in group UT was significantly decreased on PTD 5 and 7 (with t values respectively 8.317 and 15.071, P values below 0.01). (2) The proliferative activity of T lymphocytes of patients in group CT on PTD 1, 3, 5, and 7 was respectively 0.71±0.11, 0.61±0.15, 0.54±0.12, and 0.67±0.17, which was significantly lower than that in group HC (1.21±0.22, with t values from 8.686 to 11.957, P values below 0.01). The proliferative activity of T lymphocytes of patients in group UT on PTD 3, 5, and 7 were respectively 0.81±0.11, 0.85±0.14, and 1.08±0.13, which was significantly higher than that in group CT (with t values from 4.808 to 8.568, P values below 0.01). (3) Compared with those of volunteer in group HC, content of IL-2 in culture supernatant of T lymphocytes of patients in group CT was significantly decreased from PTD 1 to 7 (with t values from 8.073 to 9.288, P values below 0.01), content of IL-4 in serum of patients in group CT was significantly increased from PTD 1 to 7 (with t values from 18.926 to 41.451, P values below 0.01), and content of IFN-γ in serum of patients in group CT was significantly decreased from PTD 1 to 7 (with t values from 4.543 to 27.659, P values below 0.01). Compared with those in group CT, content of IL-2 in culture supernatant of T lymphocytes of patients in group UT was significantly increased from PTD 3 to 7 (with t values from 6.507 to 8.869, P values below 0.01), content of IL-4 in serum of patients in group UT was significantly decreased from PTD 3 to 7 (with t values from 6.922 to 8.843, P values below 0.01), and content of IFN-γ in serum of patients in group UT was significantly increased on PTD 5 and 7 (with t values respectively 5.369 and 13.521, P values below 0.01). (4) The percentages of CD14(+) monocytes with positive expression of HLA-DR of patients in group CT on PTD 1, 3, 5, and 7 were respectively (28±6)%, (25±7)%, (25±7)%, and (39±10)%, which were significantly lower than the percentage of volunteer in group HC [(87±8)%, with t values from 16.323 to 25.645, P values below 0.01]. The percentages of CD14(+) monocytes with positive expression of HLA-DR of patients in group UT on PTD 3, 5, and 7 were respectively (40±6)%, (42±9)%, and (49±10)%, which were significantly higher than those in group CT (with t values from 3.071 to 7.324, P values below 0.01).

CONCLUSIONSOn the basis of CT, additional ulinastatin intervention can decrease CD4(+) CD25(+) Tregs percentage, improve the immune function of T lymphocytes and T helper cells, and increase expression of HLA-DR on CD14(+) monocytes of patients with severe burn injury, thus improve the immune function of patients.

Burns ; drug therapy ; immunology ; Cells, Cultured ; Debridement ; Enzyme-Linked Immunosorbent Assay ; Glycoproteins ; therapeutic use ; Humans ; Interferon-gamma ; blood ; Interleukin-2 ; metabolism ; Interleukin-4 ; blood ; Monocytes ; immunology ; Skin Transplantation ; T-Lymphocytes, Regulatory ; immunology

BACKGROUNDCalpain, a calcium-dependent cysteine protease, has been demonstrated to regulate osteoclastogenesis, which is considered one of the major reasons for cancer-induced bone pain (CIBP). In the present study, calpain inhibitor was applied in a rat CIBP model to determine whether it could reduce CIBP through regulation of osteoclastogenesis activity.

METHODSA rat CIBP model was established with intratibial injection of Walker 256 cells. Then, the efficacy of intraperitoneal administered calpain inhibitor III (MDL28170, 1 mg/kg) on mechanical withdrawal threshold (MWT) of bilateral hind paws was examined on postoperative days (PODs) 2, 5, 8, 11, and 14. On POD 14, the calpain inhibitor's effect on tumor bone tartrate-resistant acid phosphatase (TRAP) stain and radiology was also carefully investigated.

RESULTSPain behavioral tests in rats showed that the calpain inhibitor effectively attenuated MWTs of both the surgical side and contralateral side hind paws on POD 5, 8, and 11 (P < 0.05). TRAP-positive cell count of the surgical side bone was significantly decreased in the calpain inhibitor group compared with the vehicle group (P < 0.05). However, bone resorption and destruction measured by radiographs showed no difference between the two groups.

CONCLUSIONSCalpain inhibitor can effectively reduce CIBP of both the surgical side and nonsurgical side after tumor injection in a rat CIBP model. It may be due to the inhibition of receptor activator of nuclear factor-kappa B ligand-induced osteoclastogenesis. Whether a calpain inhibitor could be a novel therapeutic target to treat CIBP needs further investigation.

Animals ; Bone Neoplasms ; drug therapy ; physiopathology ; Dipeptides ; therapeutic use ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; drug effects ; Glycoproteins ; therapeutic use ; Male ; Osteogenesis ; drug effects ; Pain ; drug therapy ; etiology ; Rats ; Rats, Sprague-Dawley

Drugs, Chinese Herbal ; therapeutic use ; Glycoproteins ; therapeutic use ; Humans ; Paraquat ; poisoning ; Poisoning ; drug therapy

BACKGROUNDIt was believed that inflammatory response induced by cardiopulmonary bypass (CPB) was blamed for complications after cardiac surgery. To improve the outcome, many pharmacological interventions have been applied to attenuate inflammatory response during CPB. The objective of this study was to investigate the effect of ulinastatin (urinary trypsin inhibitor [UTI]) on outcome after CPB surgery.

METHODSTotally, 208 patients undergoing elective valves replacement between November 2013 and September 2014 were divided into Group U (n = 70) and Group C (n = 138) based on they received UTI or not. Categorical variables were compared between groups using Fisher's exact test, and continuous variables using unpaired Student's t-test or Mann-Whitney U-test. One-way analysis of variance and Dunnett's or Tukey's tests were used to compare values at different time points within the same group. The risk of outcomes was estimated and adjusted by multivariable logistic regression, propensity scoring, and mixed-effect models for all measured variables.

RESULTSBoth the serious complications in total, including death, acute lung injury, acute respiratory distress syndrome and acute kidney injury, and the other complications, including hemodialysis, infection, re-incubation, and tracheotomy were similar between the two groups (P > 0.05). After adjusted by multivariable logistic regression and the propensity score, UTI still cannot be found any benefit to improve any outcomes after cardiac surgery. Also, no statistical differences with regard to duration of postoperative mechanical ventilation, the length of Intensive Care Unit and hospital stays (P > 0.05).

CONCLUSIONUTI did not improve postoperative outcomes in our patients after cardiopulmonary bypass surgery.

Acute Kidney Injury ; etiology ; Adult ; Cardiac Surgical Procedures ; adverse effects ; Cardiopulmonary Bypass ; adverse effects ; Female ; Glycoproteins ; therapeutic use ; Humans ; Length of Stay ; Male ; Middle Aged ; Postoperative Complications ; Respiratory Distress Syndrome, Adult ; etiology ; Retrospective Studies