Publications by authors named "Renyu Ding"

27 Publications

  • Page 1 of 1

Evaluation of the Molecular Mechanisms of Sepsis Using Proteomics.

Front Immunol 2021 21;12:733537. Epub 2021 Oct 21.

Department of Intensive Care Unit, The First Hospital of China Medical University, Shenyang, China.

Sepsis is a complex syndrome promoted by pathogenic and host factors; it is characterized by dysregulated host responses and multiple organ dysfunction, which can lead to death. However, its underlying molecular mechanisms remain unknown. Proteomics, as a biotechnology research area in the post-genomic era, paves the way for large-scale protein characterization. With the rapid development of proteomics technology, various approaches can be used to monitor proteome changes and identify differentially expressed proteins in sepsis, which may help to understand the pathophysiological process of sepsis. Although previous reports have summarized proteomics-related data on the diagnosis of sepsis and sepsis-related biomarkers, the present review aims to comprehensively summarize the available literature concerning "sepsis", "proteomics", "cecal ligation and puncture", "lipopolysaccharide", and "post-translational modifications" in relation to proteomics research to provide novel insights into the molecular mechanisms of sepsis.
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http://dx.doi.org/10.3389/fimmu.2021.733537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566982PMC
October 2021

Immune checkpoint molecule TIGIT manipulates T cell dysfunction in septic patients.

Int Immunopharmacol 2021 Oct 13;101(Pt B):108205. Epub 2021 Oct 13.

Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China. Electronic address:

Sepsis is a dysregulated host response to infection. T cell dysfunction results in the failure to eradicate pathogens and the increased susceptibility to nosocomial infections and mortality during sepsis. Although PD-1 has shown to be a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Here we demonstrated that the immune checkpoint molecule TIGIT on lymphocytes and the critical role of TIGIT in regulating T cell responses in sepsis. Fifty septic patients and seventeen healthy donors were prospectively enrolled. The expression patterns of TIGIT and other molecules on lymphocytes were quantitated by flow cytometry. Ex vivo functional assays were also conducted. Results show that TIGIT expression on T cells was significantly upregulated in sepsis and septic shock patients relative to healthy donors. Elevated frequencies of TIGIT T cells correlated with aggravated inflammatory response and organ injuries. Of note, TIGIT expression on CD8 T cells showed a competitive capability to predict ICU mortality in sepsis. TIGIT T cells expressed higher levels of PD-1, lower levels of CD226, and released fewer cytokines. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells from septic patients. These data illustrate that TIGIT on T cells is being used not only as a clinical predictor of poor prognosis but also as a potential target of novel immunotherapeutic intervention during sepsis.
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http://dx.doi.org/10.1016/j.intimp.2021.108205DOI Listing
October 2021

Shock in China 2018 (SIC-study): a cross-sectional survey.

Ann Transl Med 2021 Aug;9(15):1219

Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.

Background: Shock is a critical illness that seriously threatens the lives of patients. This study explains the epidemiology of shock, mortality of shock, and identify factors that related to hospital death.

Methods: This is a multi-centre cross-sectional survey, which included 1,064 tertiary hospitals in 31 provinces, municipalities, and autonomous regions across China mainland. Totally 289,428 patients who diagnosed with shock based on the ICD-10 abstracted from the Hospital Quality Monitoring System (HQMS) in 2018, a national database administrated by National Health Commission of the PRC.

Results: Patients diagnosed with shock were screened and classified according to the type of shock. Regression analysis was used to identify factors that related to death. A total of 79,668,156 medical records were included in HQMS in 2018, from which a total of 289,428 records with shock were identified. Hypovolemic shock occurred in 128,436 cases (44.38%), septic shock occurred in 121,543 cases (41.99%), cardiogenic shock occurred in 44,597 cases (15.41), and obstructive shock occurred in 3,168 cases (1.09%). Of these, 8,147 cases (2.81%) had mixed shock, which means had two or more types of shock. For all the shock cases, the top three frequent concomitant diseases recorded were circulatory system diseases (55.22%), digestive system diseases (53.64%), and respiratory system diseases (53.31%). Of the four types of shock, cases with cardiogenic shock had the highest in-hospital mortality (31.6%), followed by those with obstructive shock (25.2%), septic shock (22.9%), and hypovolemic shock (15.5%). Interestingly, the combination of shock and malignant tumors is one of the major factors that related to hospital deaths.

Conclusions: Shock is a serious disease with a high fatality rate and huge clinical costs. According to this epidemiological survey of shock in China 2018, we should clarify the factors related to the hospital death in shock cases.
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http://dx.doi.org/10.21037/atm-21-310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421935PMC
August 2021

Nutritional practice in critically ill COVID-19 patients: A multicenter ambidirectional cohort study in Wuhan and Jingzhou.

Asia Pac J Clin Nutr 2021 ;30(1):15-21

Department of Critical Care Medicine, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China. Email:

Background And Objectives: The novel coronavirus disease (COVID-19) epidemic is spreading all over the world. With the number of cases increasing rapidly, the epidemiological data on the nutritional practice is scarce. In this study, we aim to describe the clinical characteristics and nutritional practice in a cohort of critically ill COVID-19 patients.

Methods And Study Design: This is a multicenter, ambidirectional cohort study conducted at 11 hospitals in Hubei Province, China. All eligible critical COVID-19 patients in the study hospital intensive care units at 00:00, March 6th, 2020, were included. Data collection was performed via written case report forms.

Results: A total of 44 patients were identified and enrolled, of whom eight died during the 28-day outcome follow- up period. The median interval between hospital admission and the study day was 24 (interquartile range, 13- 26) days and 52.2% (23 of 44) of patients were on invasive mechanical ventilation. The median nutrition risk in critically ill (mNUTRIC) score was 3 (interquartile range, 2-5) on the study day. During the enrolment day, 68.2% (30 of 44) of patients received enteral nutrition (EN), while 6.8% (3 of 44) received parenteral nutrition (PN) alone. Nausea and aspiration were uncommon, with a prevalence of 11.4% (5 of 44) and 6.8% (3 of 44), respectively. As for energy delivery, 69.7% (23 of 33) of patients receiving EN and/or PN were achieving their prescribed targets.

Conclusions: The study showed that EN was frequently applied in critical COVID-19 patients. Energy delivery may be suboptimal in this study requiring more attention.
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http://dx.doi.org/10.6133/apjcn.202103_30(1).0003DOI Listing
April 2021

MicroRNA-34a Inhibition Alleviates Lung Injury in Cecal Ligation and Puncture Induced Septic Mice.

Front Immunol 2020 13;11:1829. Epub 2020 Aug 13.

Department of Trauma Intensive Care Unit, The First Affiliated Hospital of Hainan Medical University, Haikou, China.

Sepsis is the leading cause of death in intensive care units. MicroRNA-34a (miR-34a) is involved in sepsis progression, while its underlying mechanisms on sepsis-induced lung injury remain obscure. Oxidative stress, pyroptosis, and inhibition of autophagy can result in organ injury. MiR-34a has been reported to regulate oxidative stress and autophagy via inhibiting silent information regulator T1 (SIRT1) and autophagy gene 4B (ATG4B) signaling. This study aimed at identifying the function of miR-34a in oxidative stress, inflammation, pyroptosis, and autophagy in sepsis-induced lung injury. Male 8-week-old C57BL/6 mice were subjected to cecal ligation and puncture and treated with miR-34a antagomir/agomir. Survival ( = 10), histopathological changes ( = 6), and lung wet-to-dry ratio ( = 6) were recorded and assayed. Other detection ( = 6) was performed to investigate the level of oxidative stress, inflammation, pyroptosis, and autophagy in lung tissues. Results showed that miR-34a down-regulation ameliorated lung injury in septic mice as reflected by decreased lung injury scores (decrease from 3.00 ± 0.32 to 2.00 ± 0.32) and wet-to-dry ratio (0.36-fold decrease). MiR-34a down-regulation also decreased reactive oxygen species accumulation (0.36-fold decrease), and promoted superoxide dismutase activity and the expression of SIRT1 (1.24-fold increase), heme oxygenase-1 and nuclear factor erythroid 2 like 2 to inhibit oxidative stress in septic mice. Moreover, miR-34a down-regulation suppressed inflammatory response and pyroptosis in septic mice, as evidenced by decreased level of pro-inflammatory factors including tumor necrosis factor α, interleukin-6 (IL-6), IL-1β, and IL-18, activity of caspase-1 (0.51-fold decrease) and expression of nucleotide-binding domain and leucine-rich repeat protein-3 (0.48-fold decrease), apoptosis-associated speck-like protein containing a CARD, cleaved-caspase-1, and cleaved-gasdermin D (0.36-fold decrease), and increased level of anti-inflammatory factors IL-10. MiR-34a down-regulation also enhanced autophagy in septic mice as evidenced by more autolysosomes and elevated expressions of ATG4B (0.90-fold increase), beclin1, ATG9, and LC3 II/I. Among these experiments, miR-34a up-regulation showed opposite effects on oxidative stress, inflammatory response, pyroptosis, and autophagy in septic mice. Additionally, miR-34a could bind to the 3'-untranslated region of SIRT1 and ATG4B. In conclusion, our findings demonstrated that miR-34a was implicated in oxidative stress, inflammation, pyroptosis, and autophagy in the development of sepsis. MiR-34a inhibition had a potential to alleviate sepsis-induced lung injury.
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http://dx.doi.org/10.3389/fimmu.2020.01829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438583PMC
April 2021

Arnold-Chiari malformation type I and the posterior dislocation of the odontoid process aggravate prolonged weaning in a patient with severe viral pneumonia: a case report.

BMC Pulm Med 2020 Feb 11;20(1):37. Epub 2020 Feb 11.

Department of Intensive Care, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang, 110001, Liaoning Province, People's Republic of China.

Background: Prolonged and difficult weaning is associated with higher rates of complications and mortality. Therefore, it is important to identify the associated factors.

Case Presentation: We describe our experience with a 37-year-old man diagnosed with severe viral pneumonia (influenza A). He presented with acute respiratory failure type I on admission. During intubation, his blood pressure and heart rate decreased, and epinephrine and norepinephrine were administered. Although his clinical condition improved 8 days after intensive care unit (ICU) admission, he experienced difficulty weaning. He remained conscious but had a poor spontaneous cough with sputum production and weak limb muscle strength. His cough reflex was absent during bronchoscopic sputum suction, and he used abdominal breathing during the T-tube test. Magnetic resonance imaging revealed an Arnold-Chiari malformation type I, posterior dislocation of the odontoid process, and syringomyelia, with compression and deformation of the medulla and high cervical cord. The patient was successfully weaned from the ventilator at 20 days after ICU admission.

Conclusions: Arnold-Chiari malformation type I and posterior dislocation of the odontoid process, which aggravate medullary compression and increase the risk of cervical nerve injury, might be a rare factor affecting prolonged weaning in critical illness.
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http://dx.doi.org/10.1186/s12890-020-1078-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014774PMC
February 2020

Effects of antiplatelet therapy on the mortality rate of patients with sepsis: A meta-analysis.

J Crit Care 2019 04 5;50:162-168. Epub 2018 Dec 5.

Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China. Electronic address:

Purpose: Abnormal platelet activation plays an important role in the development of sepsis. The effect of antiplatelet drugs on the outcome of patients with sepsis remains unclear. This meta-analysis aimed to determine the effect of antiplatelet drugs on the prognosis of patients with sepsis.

Materials And Methods: PubMed, Cochrane Library, CBM, and Embase were searched for all related articles published from inception to April 2018. The primary end point was mortality. Adjusted data were used and statistically analysed.

Results: Ten cohort studies were included. The total number of patients with sepsis was 689,897. Data showed that the use of antiplatelet drugs could effectively reduce the mortality of patients with sepsis (odds ratio (OR) = 0.82, 95% CI: 0.81-0.83, p < 0.05). Seven studies used aspirin for antiplatelet therapy, and subgroup analysis showed that aspirin effectively reduced ICU or hospital mortality in patients with sepsis (OR = 0.60, 95% CI: 0.53-0.68, p < 0.05). A subgroup analysis on the timing of anti-platelet drug administration showed that antiplatelet drugs can reduce mortality when administered either before (OR = 0.78, 95% CI: 0.77-0.80) or after sepsis (OR = 0.59, 95% CI: 0.52-0.67).

Conclusions: Antiplatelet drugs, particularly aspirin, could be used to effectively reduce mortality in patients with sepsis.
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http://dx.doi.org/10.1016/j.jcrc.2018.12.004DOI Listing
April 2019

Birth Weight and Risk of Type 2 Diabetes Mellitus, Cardiovascular Disease, and Hypertension in Adults: A Meta-Analysis of 7 646 267 Participants From 135 Studies.

J Am Heart Assoc 2018 12;7(23):e008870

5 Department of Epidemiology and Biostatistics School of Public Health Peking University Beijing China.

Background Low birth weight has been associated with increased risk of type 2 diabetes mellitus, cardiovascular disease, and hypertension, but the risk at high birth weight levels remains uncertain. This systematic review and meta-analysis aimed to clarify the shape of associations between birth weight and aforementioned diseases in adults and assessed sex-specific risks. Methods and Results We systematically searched PubMed, EMBASE , and Web of Science for studies published between 1980 and October 2016. Studies of birth weight and type 2 diabetes mellitus (T2 DM ), cardiovascular disease ( CVD ), and hypertension were included. Random-effects models were used to derive the summary relative risks and corresponding 95% confidence intervals.We identified 49 studies with 4 053 367 participants assessing the association between birth weight and T2 DM , 33 studies with 5 949 477 participants for CVD , and 53 studies with 4 335 149 participants for hypertension and high blood pressure. Sex-specific binary analyses showed that only females had an increased risk of T2 DM and CVD at the upper tail of the birth weight distribution. While categorical analyses of 6 birth weight groups and dose-response analyses showed J-shaped associations of birth weight with T2 DM and CVD , the association was inverse with hypertension. The lowest risks for T2 DM , CVD , and hypertension were observed at 3.5 to 4.0, 4.0 to 4.5, and 4.0 to 4.5 kg, respectively. Conclusions These findings indicate that birth weight is associated with risk of T2 DM and CVD in a J-shaped manner and that this is more pronounced among females.
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http://dx.doi.org/10.1161/JAHA.118.008870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405546PMC
December 2018

Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury.

Respir Res 2018 Nov 15;19(1):220. Epub 2018 Nov 15.

Department of Intensive Care Unit, The First Affiliated Hospital of China Medical University, No. 92 Bei-er Road, Shenyang, 110001, Liaoning Province, People's Republic of China.

Background: Endothelial barrier dysfunction is central to the pathogenesis of sepsis-associated acute lung injury (ALI). Microtubule (MT) dynamics in vascular endothelium are crucial for the regulation of endothelial barrier function. Unfractionated heparin (UFH) possesses various biological activities, such as anti-inflammatory activity and endothelial barrier protection during sepsis.

Methods: Here, we investigated the effects and underlying mechanisms of UFH on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. C57BL/6 J mice were randomized into vehicle, UFH, LPS and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received intravenous UFH 0.5 h prior to LPS injection. Human pulmonary microvascular endothelial cells (HPMECs) were cultured for analyzing the effects of UFH on LPS-induced and nocodazole-induced hyperpermeability, F-actin remodeling, and LPS-induced p38 MAPK activation.

Results: UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes, and increased the lung W/D ratio and Evans blue accumulation in vivo. Both in vivo and in vitro studies showed that UFH pretreatment blocked the LPS-induced increase in guanine nucleotide exchange factor (GEF-H1) expression and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, and microtubule (MT) disassembly in LPS-induced ALI mouse model and human pulmonary microvascular endothelial cells (HPMECs). These results suggested that UFH ameliorated LPS-induced endothelial barrier dysfunction by inhibiting MT disassembly and GEF-H1 expression. In addition, UFH attenuated LPS-induced hyperpermeability of HPMECs and F-actin remodeling. In vitro, UFH pretreatment inhibited LPS-induced increase in monomeric tubulin expression and decrease in tubulin polymerization and acetylation. Meanwhile, UFH ameliorates nocodazole-induced MTs disassembly and endothelial barrier dysfunction.Additionally, UFH decreased p38 phosphorylation and activation, which was similar to the effect of the p38 MAPK inhibitor, SB203580.

Conclusions: UFH exert its protective effects on pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization and is associated with the p38 MAPK pathway.
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http://dx.doi.org/10.1186/s12931-018-0925-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238311PMC
November 2018

The Epidemiology of Symptomatic Catheter-associated Urinary Tract Infections in the Intensive Care Unit: A 4-year Single Center Retrospective Study.

Urol J 2019 06 17;16(3):312-317. Epub 2019 Jun 17.

Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, P.R. China.

Purpose: Catheter-associated urinary tract infection (CAUTI) occurs frequently in critical illness with signifi-cant morbidity, mortality, and additional hospital costs. The epidemiology of symptomatic ward-acquired CAUTI (within 48 hours of intensive care unit [ICU] admission) has not been carefully examined. The objective of our study was to identify the patient characteristics and microbiology of symptomatic CAUTI in critical illness.

Materials And Methods: A 4-year retrospective observational study (2013-2016) was conducted at a single adult ICU with 30 beds in a tertiary hospital in Northeast China. The enrolled patients were over 18 years of age and had been diagnosed as having symptomatic CAUTIs in the ICU from January 2013 to December 2016. The infor-mation of clinicopathological characteristics (such as age, sex, underlying diseases, hospital admission diagnosis, ICU admission source, severity of illness, duration of urinary catheterization, use of antibiotics, duration of ICU stay, and ICU mortality) was recorded in an electronic database by senior clinicians who were blinded to the study purpose and design. Microbiological data were retrieved from the computerized hospital database.

Results: Between January 2013 and December 2016, 4115 patients were admitted to the ICU. Ninety-eight symp-tomatic CAUTI cases were enrolled in this study, including 29 patients who had ward-acquired CAUTI and 69 pa-tients who had ICU-acquired CAUTI. Patients with ward-acquired symptomatic CAUTI had significantly shorter overall ICU length of stay and shorter urinary catheterization time, and the overall ICU mortality was significantly higher in patients who had ICU-acquired symptomatic CAUTI. More third-generation cephalosporins and carbap-enems were used prior to CAUTI in the patients with ICU-acquired symptomatic CAUTI. Escherichia coli and Acinetobacter baumannii were the most common bacteria causing ward-acquired and ICU-acquired CAUTI, re-spectively. There were a higher number of cases of non-Candida albicans infections in patients with ICU-acquired symptomatic CAUTI than in patients with ward-acquired symptomatic CAUTI.

Conclusion: Clinical characteristics, microbiological characteristics, and prognosis were different between ward-acquired and ICU-acquired symptomatic CAUTI. Patients with ICU-acquired symptomatic CAUTI had higher overall ICU mortality.
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http://dx.doi.org/10.22037/uj.v0i0.4256DOI Listing
June 2019

Comparison of a new criteria for sepsis-induced coagulopathy and International Society on Thrombosis and Haemostasis disseminated intravascular coagulation score in critically ill patients with sepsis 3.0: a retrospective study.

Blood Coagul Fibrinolysis 2018 Sep;29(6):551-558

Department of Intensive Care Unit, The First Hospital of China Medical University, Shenyang, Liaoning Province, PR China.

: Recently, new criteria for sepsis-induced coagulopathy (SIC) were developed, including the sequential organ failure assessment (SOFA) criteria. The objective of this study was to evaluate the new SIC criteria in patients diagnosed with sepsis 3.0. Data from patients diagnosed with sepsis 3.0 after ICU admission were retrospectively obtained from July 2013 to June 2014. Relevant demographic, clinical, and laboratory parameters were noted. This study included 252 patients. The International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC), modified ISTH-DIC, and SIC scores were higher among nonsurvivors (P < 0.0001). The Acute Physiology and Chronic Health Evaluation II (P < 0.001), ISTH (P = 0.001), modified ISTH (P = 0.001), and SIC scores (P = 0.007) were independent predictors of ICU mortality. Using the receiver operating characteristic curve, SOFA had the greatest power for predicting ICU mortality; ISTH or modified ISTH score had greater predictive power than the SIC score. There were strong correlations between SIC score and ISTH (P < 0.0001), modified ISTH (P < 0.0001), the Acute Physiology and Chronic Health Evaluation II (P = 0.012), and SOFA (P < 0.0001) scores. More nonsurvivors were diagnosed with DIC using the ISTH and modified ISTH criteria (P < 0.001). In contrast, there was no significant difference in the proportion of patients with SIC between both groups (P = 0.055). ISTH score, modified ISTH score, and SIC score were independent risk factors for ICU mortality. Compared with the ISTH and modified ISTH scores, SIC score showed no advantage in diagnosing sepsis-associated coagulopathy or DIC. The application of these three criteria in patients with sepsis 3.0 needs further evaluation.
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http://dx.doi.org/10.1097/MBC.0000000000000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133197PMC
September 2018

The Central Role of the Inflammatory Response in Understanding the Heterogeneity of Sepsis-3.

Biomed Res Int 2018 7;2018:5086516. Epub 2018 Jun 7.

Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang, Liaoning Province 110001, China.

In sepsis-3, in contrast with sepsis-1, the definition "systemic inflammatory response" has been replaced with "dysregulated host response", and "systemic inflammatory response syndrome" (SIRS) has been replaced with "sequential organ failure assessment" (SOFA). Although the definition of sepsis has changed, the debate regarding its nature is ongoing. What are the fundamental processes controlling sepsis-induced inflammation, immunosuppression, or organ failure? In this review, we discuss the heterogeneity of sepsis-3 and address the central role of inflammation in the pathogenesis of sepsis. An unbalanced pro- and anti-inflammatory response, inflammatory resolution disorder, and persistent inflammation play important roles in the acute and/or chronic phases of sepsis. Moreover, powerful links exist between inflammation and other host responses (such as the neuroendocrine response, coagulation, and immunosuppression). We suggest that a comprehensive evaluation of the role of the inflammatory response will improve our understanding of the heterogeneity of sepsis.
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http://dx.doi.org/10.1155/2018/5086516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011097PMC
January 2019

Platelet activation and antiplatelet therapy in sepsis: A narrative review.

Thromb Res 2018 06 9;166:28-36. Epub 2018 Apr 9.

Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China. Electronic address:

Platelet activation plays an important role in the development of sepsis. During sepsis, platelet activation leads to endothelial cell injury and promotes neutrophil extracellular trap and microthrombus formation, exacerbating septic coagulation and inflammatory reactions. The resultant induction or aggravation of disseminated intravascular coagulation (DIC) leads to organ damage. Antiplatelet drugs can inhibit coagulation and inflammatory reactions in models of sepsis, reducing damage to organ function. Clinical studies suggest that aspirin may improve the prognosis of patients with sepsis. In conclusion, antiplatelet drugs are promising agents that can improve the prognosis of sepsis patients and are expected to become a new line of treatment. However, further clinical studies are required for validation.
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http://dx.doi.org/10.1016/j.thromres.2018.04.007DOI Listing
June 2018

Diet/lifestyle and risk of diabetes and glycemic traits: a Mendelian randomization study.

Lipids Health Dis 2018 Jan 29;17(1):18. Epub 2018 Jan 29.

Department of Otolaryngology, The First Hospital of China Medical University, Liaoning, 110001, China.

Background: Observational studies have demonstrated diet/lifestyle play roles in development of type 2 diabetes (T2DM); however, it remains unclear whether these relationships are causal.

Methods: A two-sample MR approach was used to examine the causal effect of diet/lifestyle upon risk of T2DM and glycemic traits.

Results: The protein intake-increasing allele C of FTO was significant associated with higher risk of T2DM (Beta ± SE = 0.104 ± 0.014, P = 4.40 × 10), higher level of HOMA-IR (Beta ± SE = 0.016 ± 0.004, P = 9.55 × 10), HOMA-B (Beta ± SE = 0.008 ± 0.003, P = 0.020). Using MR analyses, increased protein intake was causally associated with an increased risk of T2DM (Beta ± SE = 0.806 ± 0.260, P = 0.002). In addition, smoking cessation was causally associated with increased levels of glycemic traits such as HOMA-IR (Beta ± SE = 0.165 ± 0.072, P = 0.021), fasting insulin (Beta ± SE = 0.132 ± 0.066, P = 0.047) and fasting glucose (Beta ± SE = 0.132 ± 0.064, P = 0.039).

Conclusions: These results provide evidence supporting a causal role for higher protein intake and smoking cession in T2DM. Our study provides further rationale for individuals at risk for diabetes to keep healthy lifestyle.
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http://dx.doi.org/10.1186/s12944-018-0666-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787924PMC
January 2018

Unfractionated heparin protects the protein C system against lipopolysaccharide-induced damage and .

Exp Ther Med 2017 Dec 29;14(6):5515-5522. Epub 2017 Sep 29.

Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis-associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)-induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR using human umbilical vein endothelial cells (HUVECs). The data indicated that UFH preconditioning attenuated the decline in circulating activated protein C following LPS administration, and also reduced LPS-induced shedding of TM and EPCR. In HUVECs, LPS stimulation led to the downregulation of TM and EPCR expression, and UFH dose-dependently restored the mRNA and protein levels of TM and EPCR. In addition, UFH inhibited the LPS-induced activation of mitogen-activated protein kinase 14, proto-oncogene tyrosine-protein kinase Src and nuclear factor κB signaling in HUVECs. In summary, these results suggest that UFH has a protective effect on the protein C system during sepsis. Thus, UFH may be a candidate therapeutic agent for the treatment of patients with sepsis.
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http://dx.doi.org/10.3892/etm.2017.5236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740512PMC
December 2017

Lipopeptide PAM3CYS4 Synergizes N-Formyl-Met-Leu-Phe (fMLP)-Induced Calcium Transients in Mouse Neutrophils.

Shock 2018 10;50(4):493-499

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

N-Formyl-Met-Leu-Phe (fMLP), a mimic of N-formyl oligopeptides that are released from bacteria, is a potent leukocyte chemotactic factor. It induces intracellular calcium ([Ca]i) transient that is important for various neutrophil biological functions, e.g., adhesion, ROS, and cytokine productions. Toll-like receptors (TLRs), an essential part of host innate immunity, regulate neutrophil activities, but their role in [Ca]i signaling is less clear. In the present study, we examined the effect of several TLR ligands, including Pam3Cys4 (TLR1/2), lipopolysaccharide (LPS, TLR4), and lipoteichoic acid (LTA, TLR2/6), on calcium signaling and on the fMLP-induced [Ca]i transients in mouse neutrophils loaded with Fura-2/AM. We found that unlike fMLP, the three TLR ligands tested did not elicit any detectable Ca flux. However, Pam3Cys4, but not LPS or LTA, markedly synergized the fMLP-induced [Ca]i transients, and had no effect on the host component keratinocyte-derived cytokine (KC)- or C5a-induced calcium flux. The effect of Pam3Cys4 on the fMLP-induced [Ca]i transients is by enhancing extracellular Ca influx, not intracellular Ca release. Surprisingly, deletion of TLR2 or MyD88 in neutrophils had no impact on the Pam3Cys4's effect, suggesting a TLR2-MyD88-independent mechanism. Finally, using the pan PKC activator and inhibitor, we demonstrated that PKC negatively regulated fMLP-induced [Ca]i transients and that inhibition of PKC did not prohibit Pam3Cys4's synergistic effect on the fMLP-induced calcium influx. In conclusion, the present study identified a novel synergistic effect of Pam3Cys4 on fMLP-induced [Ca]i transients, a process important for many neutrophil biological functions.
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http://dx.doi.org/10.1097/SHK.0000000000001062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464634PMC
October 2018

Rho-kinase inhibitor treatment prevents pulmonary inflammation and coagulation in lipopolysaccharide-induced lung injury.

Thromb Res 2017 Feb 24;150:59-64. Epub 2016 Dec 24.

Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China. Electronic address:

Introduction: In the pathogenesis of sepsis-induced acute lung injury (ALI), the crosstalk between inflammation and coagulation plays a pivotal role. The aim of this study was to investigate the role of Rho kinase (ROCK) inhibitor in alleviating pulmonary inflammation and coagulation in lipopolysaccharide (LPS)-induced acute lung injury (ALI) models.

Methods: In the in vivo study, mice were randomized to four different groups: Control, Y-27632 (Y), LPS, and LPS+Y-27632 (LPS+Y). ALI was induced by intranasally administering LPS (10μg in 50μL PBS). Y-27632 (10mg/kg body weight,) was injected intraperitoneally at 18h and 1h before LPS challenge. Mice were euthanized at 3h or 8h post LPS challenge (N=8 per group). In the in vitro study, human pulmonary microvascular endothelial cells (HPMECs) were incubated with LPS alone (1μg/mL) or in combination with 10μM Y-27632 or 50μM BAY11-7082. Cells were pretreated with the inhibitors 30min before exposure to LPS. Three hours later, cells were isolated for subsequent analysis.

Results: The myeloperoxidase (MPO) activity and fibrinogen deposits in the lung tissue significantly decreased and the lung damage in ALI mouse was attenuated. Pretreatment with Y-27632 markedly reduced the LPS-induced expression of interleukins 1β and 6, and the activation of nuclear factor (NF)-κB. Furthermore, ROCK inhibitor treatment antagonized the expression of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue and HPMECs.

Conclusions: ROCK inhibition protects against the endotoxin-induced pulmonary inflammation and coagulation via NF-kappaB pathway modulation.
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http://dx.doi.org/10.1016/j.thromres.2016.12.020DOI Listing
February 2017

Pretreatment with Rho-kinase inhibitor ameliorates lethal endotoxemia-induced liver injury by improving mitochondrial function.

Int Immunopharmacol 2016 Nov 30;40:125-130. Epub 2016 Aug 30.

Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China. Electronic address:

Rho kinase (ROCK) inhibition has been reported to improve various inflammatory diseases including endotoxemia. Mitochondrial dysfunction might be the key to the pathophysiology of sepsis-induced organ failure. Therefore, this study aimed to explore whether ROCK inhibition protects against the liver injury by regulating mitochondrial function in endotoxemia model mice. The mice were randomly divided into four groups (N=6-8 per group): control, LPS, LPS+Y-27632 (LPS+Y), and LPS+Mito-TEMPO (LPS+M). For induction of endotoxin-induced acute liver injury, the mice were intraperitoneally administered lipopolysaccharide (LPS, 20mg/kg). The ROCK inhibitor Y-27632 (or mitochondrial antioxidant Mito-TEMPO) was intraperitoneally administered at 18 and 1h before injection of LPS. The mice were euthanized 8h after LPS administration. The liver and blood samples were taken and preserved for analysis. Results of this study showed that pretreatment with Y-27632 or Mito-TEMPO significantly attenuated the liver injury as compared to the LPS group. This was confirmed by decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and by reduced hepatocellular apoptosis and histologic damage. Pretreatment with Y-27632 or Mito-TEMPO markedly reduced the LPS-induced inflammatory response and oxidative stress the in liver. Furthermore, it showed similar protective effects on the hepatic mitochondrial function, including an increased activity of complexes I and IV and mitochondrial superoxide dismutase (MnSOD), and an upregulated expression of mtDNA-encoded genes. Taken together, these data demonstrate that Mito-TEMPO can potently inhibit the endotoxin-induced mitochondrial and hepatic abnormalities and indicate that mitochondrial dysfunction might play a key role in the endotoxemia-induced acute liver injury. Moreover, our study shows that ROCK inhibition protects against the endotoxemia-induced liver injury by improving the mitochondrial function.
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http://dx.doi.org/10.1016/j.intimp.2016.08.036DOI Listing
November 2016

[Persistent inflammation immunosuppression catabolism syndrome: a special type of chronic critical illness].

Zhonghua Wei Chang Wai Ke Za Zhi 2016 Jul;19(7):734-6

Department of Critical Illness, The First Hospital of China Medical University, Shenyang 110001, China.

After the concept of "chronic critical illness (CCI)" was proposed, the new concept persistent inflammation immunosuppression catabolism syndrome (PICS) is present recently. Patients with PICS are manifested by fast decreasing body weight, poor nutritional status, long-term immunosuppression and repeated nosocomial infections. These patients are faced with great challenges of persistent inflammation, acquired immunosuppression and high catabolism, which finally results in repeated nosocomial infections, prolonged hospital stay and increased mortality. At present, main problems of PICS diagnosis standard include varying length of ICU stay, difference in normal C reactive protein value, poor value of nutrition indexes, absence of clinical verification. Though associated pathophysiology mechanism is not clear, PICS is preventable and magageable with certain therapy, including early comprehensive prevention and treatment focused on infection control for CCI patients to stop the progression of PICS, application of immune modulator to improve immune function and prognosis of patients, and reasonable nutritional support and treatment. Besides, through the analysis of the association between PICS and CCI, authors draw a conclusion that PICS is a new phenotype of CCI, and immune paralysis is its main feature.
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July 2016

[Heparin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nitric oxide synthase and transforming growth factor -β/Smad signaling pathway].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2014 Nov;26(11):810-4

Department of Critical Care Medicine, Tianjin Hospital, Tianjin 300210, China, Corresponding author: Ma Xiaochun, Department of Critical Care Medicine, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China, Email:

Objective: To investigate whether heparin has a beneficial effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats, and to explore the possible underlying mechanisms.

Methods: Thirty-two adult Sprague-Dawley (SD) rats were randomly assigned into the control, heparin control, model, and heparin treatment groups, with 8 in each group. ALI rat model was reproduced by intratracheal instillation of LPS at a dose of 1 mg/kg. The rats in the control and heparin control groups received an equal volume of normal saline at the same times. The rats in the heparin control and heparin treatment groups were intravenously received 50 U/kg heparin every 1 hour after the induction of ALI. Animals were sacrificed 24 hours after LPS challenge. Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected. Histopathological evaluation, lung wet/dry (W/D) ratio, malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of inflammatory factor in BALF. Expression of inducible nitric oxide synthase (iNOS) mRNA in the lung of rats was measured by reverse transcription-polymerase chain reaction (RT-PCR). Western Blot was used to determine the expression of transforming growth factor-β1 (TGF-β1) and phosphorylation of Smad in the lung tissues. The expression of iNOS in lung was determined by immunohistochemistry.

Results: In the control and heparin control groups, lung tissue showed a normal structure and clear pulmonary alveoli under a light microscope. In the model group, ALI characters such as extensive thickening of the alveolar wall, significant infiltration of inflammatory cells, demolished structure of pulmonary alveoli, and hemorrhage were found. In the heparin treatment group, heparin treatment markedly alleviated LPS-induced these pathological changes in lung. Compared with control and heparin control groups, lung W/D ratio, lung MDA, NO and MPO levels, and tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in BALF in the model group were increased significantly. Compared with the model group, lung W/D ratio, lung MDA, NO and MPO levels, and TNF-α and IL-6 in BALF in the heparin treatment group were significantly decreased [W/D ratio: 7.54 ± 0.17 vs. 10.69 ± 0.15,MDA (mmol/mg): 2.01 ± 0.30 vs. 2.51 ± 0.25, NO (μmol/L): 3.07 ± 0.21 vs. 3.89 ±0.14,MPO (U/g): 1.94 ± 0.09 vs. 2.74 ± 0.20, TNF-α (μg/L): 201.80 ± 0.27 vs. 297.53 ± 0.34,IL-6 (μg/L): 38.41 ± 0.25 vs. 46.31 ± 0.31,all P<0.05]. RT-PCR showed that the expression of iNOS mRNA in the heparin treatment group was significantly lower than that in the model group (2 (-Δ ΔCt): 3.04 ± 0.18 vs. 4.37 ± 0.15, P < 0.05). Western Blot showed that compared with control group, the protein expressions of iNOS and TGF-β1, and phosphorylation of Smad2 and Smad3 were significantly increased, and the heparin could inhibit the protein expressions compared with model group. Immunohistochemistry showed that positive expressions of iNOS in alveolar epithelial cell and capillary endothelial cell in the heparin treatment group were significantly lower than those in the model group.

Conclusions: Heparin significantly ameliorated the lung injury induced by LPS in rats via the inhibition of nitric oxide synthase expression and the TGF-β/Smad pathway.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2014.11.009DOI Listing
November 2014

[Correlation of intestinal fatty acid binding protein and intestinal injury in severe sepsis].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2014 Jun;26(6):420-4

Department of Critical Care Medicine, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China. Corresponding author: Ma Xiaochun, Email:

Objective: To investigate the content of intestinal fatty acid binding protein (IFABP) and its clinical significance in patients with severe sepsis.

Methods: A prospective observational study was conducted. Fifty patients with severe sepsis admitted to intensive care unit (ICU) of the First Affiliated Hospital of China Medical University from July to December 2012 were enrolled, and 20 healthy patients served as control group. The concentrations of serum IFABP, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined with enzyme-linked immunosorbent assay (ELISA) on days 0, 1 and 3 after ICU admission. Acute physiology and chronic health evaluation II (APACHEII) and sequential organ failure assessment (SOFA) score, 28-day prognosis, acute gastrointestinal injury (AGI) grade were recorded at the same time. Furthermore, the contents of IFABP were compared between control group and the severe sepsis group, abdominal infection group and non-abdominal infection group, the survival group and the death group, as well as among different AGI-grade groups. Correlation analysis of IFABP and inflammatory factors, IFABP and two scores, and IFABP and time of stay in ICU and mechanical ventilation were studied. Multivariate logistic regression and analysis of 28-day outcome of the patients were also studied.

Results: IFABP levels were increased in severe sepsis patients on days 0, 1 and 3 compared with those of healthy control group (731.90±53.91 mg/L, 592.07 ± 41.94 mg/L, 511.85 ± 47.97 mg/L vs. 439.88 ± 23.68 mg/L, all P=0.000). There was no statistical significance of IFABP levels between abdominal infection group and non-abdominal infection group, the survival group and the death group, or among different AGI-grade groups. The correlation analysis showed that IFABP was statistically related with IL-6 (r=0.794, P=0.000), TNF-α (r=0.878, P=0.010), APACHEII score (r=0.428, P=0.000) in patients with severe sepsis. Significant correlations were also found between IFABP and IL-6 (r=0.812, P=0.000), TNF-α (r=0.885, P=0.000) in abdominal infection group, as well as in non-abdominal infection group (IL-6: r=0.739, P=0.000; TNF-α: r=0.828, P=0.000). As shown by multivariate logistic regression analysis, SOFA scores on days 0, 1, 3 were the independent risk factors for death [odds ratio (OR) was 1.624 (P=0.004), 1.411 (P=0.027), 1.740 (P=0.012), respectively], but IFABP level, AGI grade, and APACHEII score had no influence on death rate.

Conclusions: IFABP concentrations in patients with severe sepsis were significantly increased, and it is correlated well to IL-6, TNF-α and APACHEII score, but did not related obviously with AGI grade and the prognosis of the patients.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2014.06.011DOI Listing
June 2014

Unfractionated heparin attenuates lung vascular leak in a mouse model of sepsis: role of RhoA/Rho kinase pathway.

Thromb Res 2013 Jul 6;132(1):e42-7. Epub 2013 Apr 6.

Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, China.

Introduction: Excessive vascular permeability is a characteristic feature of ALI. We have previously demonstrated that UFH prevents LPS-induced disruption of endothelial barrier function in vitro. It was the objective of this study to determine whether UFH may attenuate endotoxin-induced lung vascular leak in mice and to further explore the possible underlying mechanisms.

Methods: C57BL/6J mice were randomly divided into the control, LPS and LPS plus UFH groups. Sepsis was induced by intraperitoneal injection of LPS at a dose of 30 mg/kg. Mice in the LPS plus UFH group were intravenously received 8 units UFH (heparin sodium) diluted in 20 μl sterile saline at 0.5 h before the injection of LPS.

Results: 1) UFH pretreatment attenuated LPS-induced histopathological changes in Lung at 6 h; 2) Pretreatment of mice with UFH ameliorated LPS-induced lung edema and lung vascular leak at 6 h; 3) UFH pretreatment dramatically inhibited RhoA and ROCK activation in the lung tissues of LPS-treated mice (3 and 6 h). 4) UFH pretreatment significantly down-regulated ROCK1 gene expression, but did not affect the increased expression of ROCK2 mRNA in the lung tissues of LPS-treated mice at 3 or 6 h.

Conclusion: These data suggest that UFH may attenuate endotoxin-induced lung vascular leak by regulating RhoA/Rho kinase pathway.
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http://dx.doi.org/10.1016/j.thromres.2013.03.010DOI Listing
July 2013

Heparin rescues sepsis-associated acute lung injury and lethality through the suppression of inflammatory responses.

Inflammation 2012 Dec;35(6):1825-32

Department of Intensive Care Medicine, First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang 110001, China.

Heparin, a potent blood anticoagulant, is known to possess anti-inflammatory activity. In this work, we investigated whether heparin can ameliorate acute lung injury and lethal response in lipopolysaccharide (LPS)-induced mouse model of sepsis. We found that heparin effectively rescued lethality, improved lung pathological changes, inhibited myeloperoxidase (MPO) activity, and reduced malondialdehyde (MDA) level, lung wet/dry weight ratio and Evans blue values in LPS-induced septic mice. In addition, heparin also inhibited the release of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and IL-1β in serum and decreased the expression of p-p38, nuclear factor κB (NF-κB) and p-c-SRC kinase in lungs of septic mice. Our findings suggest that heparin is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the notion that heparin may be a potential therapeutic agent for the conditions associated with septic shock.
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http://dx.doi.org/10.1007/s10753-012-9503-0DOI Listing
December 2012

Heparin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nitric oxide synthase and TGF-β/Smad signaling pathway.

Thromb Res 2012 Apr 26;129(4):479-85. Epub 2011 Oct 26.

Department of Intensive Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, People's Republic of China.

Introduction: Heparin, a potent blood anticoagulant, has been shown to exert a variety of pharmacological activities. The purpose of this study was to investigate whether heparin has a beneficial effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and to further explore the possible underlying mechanisms.

Materials And Methods: Adult Sprague-Dawley rats were randomly assigned into the control, heparin, LPS, and LPS plus heparin groups. ALI was induced by intratracheal instillation of LPS at a dose of 1 mg/kg. Rats in the LPS plus heparin group were intravenously received 50 U/ kg heparin every 1 h after the induction of ALI.

Results: We found that heparin significantly improved LPS-induced lung pathological changes, inhibited myeloperoxidase (MPO) activity, and reduced malondialdehyde (MDA) level and lung wet/dry weight ratio. Heparin also inhibited the release of tumor necrosis factor (TNF)-α and interleukin (IL)-6, and markedly decreased the expression of inducible nitric oxide synthase (iNOS) in lung tissues and thus prevented nitric oxide (NO) release in response to LPS challenge. Additionally, heparin decreased the expression of transforming growth factor-β1 (TGF-β1), p-Smad 2, and p-Smad 3, which are all important molecules of the TGF-β1/Smad signaling pathway.

Conclusions: Heparin significantly ameliorated the lung injury induced by LPS in rats via the inhibition of nitric oxide synthase expression and the TGF-β/Smad pathway. Heparin may be a potential therapeutic reagent for treating ALI in the future.
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http://dx.doi.org/10.1016/j.thromres.2011.10.003DOI Listing
April 2012

Treatment with unfractionated heparin attenuates coagulation and inflammation in endotoxemic mice.

Thromb Res 2011 Dec 17;128(6):e160-5. Epub 2011 Aug 17.

Departments of Intensive Care Unit, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.

Introduction: In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. In addition to the anticoagulant activity, unfractionated heparin (UFH) has important immunomodulatory properties. However, different studies have reported conflicting effects on sepsis in association with heparin. The objective of this study is to determine whether UFH is able to reduce endotoxin-induced inflammation and coagulation in mice or produce improved outcome.

Methods: C57BL/6J mice were randomly divided into two groups. Experimental mice were given intravenous injection of 8 units/20 g body weight UFH (heparin sodium) diluted in 20 μl sterile saline while the control mice received vehicle sterile saline only. They were injected with LPS (30 mg/kg, i.p.) 0.5h later. Blood was collected and Livers were harvested at 3 and 6h for analysis. In survival studies, a separate group of mice were treated with 8 units/20 g UFH (n=20) or sterile saline (n=20) given intravenously at 1, 12, 24 and 36 hours after LPS injection. Mice were monitored every 12 hours for a maximum of 72 hrs.

Results: 1) Pretreatment of mice with UFH strongly reduced the levels of TNF-α, IL-1β and TAT in plasma at 3 and 6h; 2) Pretreatment of mice with UFH inhibited the expression of TNF-α, IL-1β and tissue factor genes in blood cells at 3h; 3) UFH pretreatment dramatically diminished LPS-induced neutrophil sequestration (at 3 and 6h) , thrombi formation and fibrin(ogen) deposition in the liver (at 6h). 4) The UFH-pretreated group exhibited significantly lower levels of ALT and CRE at 6h. 5) Treatment with UFH could prevent mortality associated with endotoxin challenge.

Conclusion: These data suggest that UFH attenuates inflammation and coagulation and prevents lethality in endotoxemic mice.
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http://dx.doi.org/10.1016/j.thromres.2011.07.044DOI Listing
December 2011

Sphingosine-1-phosphate attenuates lung injury induced by intestinal ischemia/reperfusion in mice: role of inducible nitric-oxide synthase.

Inflammation 2012 Feb;35(1):158-66

Department of Intensive Care Unit, The First Affiliated Hospital of China Medical University, Bei-er Rd 92, Shenyang, 110001, Liaoning Province, China.

Multiple organ failure, including acute lung injury (ALI), is a common complication of intestinal ischemia/reperfusion (I/R) injuries and contributes to its high mortality rate. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that enhances vascular barrier function and has anti-inflammatory effects. In the current study, we investigated the effect of S1P on lung injury induced by intestinal I/R. Mice were randomly assigned to one of the following groups: (1) sham-operated mice, (2) mice exposed to superior mesenteric artery occlusion for 45 min followed by reperfusion for 6 h, or (3) mice exposed to I/R that received S1P (100 μg/kg, administered by peritoneal injection). S1P markedly attenuated lung injury, manifested by the improvement of histological changes and significant decreases of lung water content. Moreover, S1P markedly reduced MDA levels and MPO activity in the lung tissues, and plasma levels of proinflammatory cytokines. In addition, S1P treatment significantly suppressed NO generation accompanied by down-regulation of iNOS expression. The results indicate that S1P has a protective effect on lung injury induced by I/R, which may be related to its suppression of iNOS-induced NO generation. S1P seems to be an effective therapeutic agent for intestinal I/R-related lung injury.
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http://dx.doi.org/10.1007/s10753-011-9301-0DOI Listing
February 2012
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