scholarly journals Mechanism by Which Tong Xie Yao Fang Heals the Intestinal Mucosa of Rats with Ulcerative Colitis through the Hippo Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wenli You ◽  
Zitong Xu ◽  
Aiting Di ◽  
Penglin Liu ◽  
Chengjian Pang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Intestinal Mucosa ◽  
Late Stage ◽  
Early Stage ◽  
Hippo Pathway ◽  
Control Group ◽  
Trinitrobenzene Sulfonic Acid ◽  
Group Model ◽  
Colon Mucosa ◽  
The Hippo Pathway

Objective. Tong Xie Yao Fang (TXYF) is a classic and effective prescription in traditional Chinese medicine which is used to treat ulcerative colitis (UC). Our study investigated the effect of TXYF on Hippo pathway activation in UC-induced intestinal mucosa injury and explored the possible mechanism. Method. After ulcerative colitis was successfully induced by trinitrobenzene sulfonic acid (TNBS), 48 Sprague Dawley (SD) rats were randomly divided into a control group, model group, TXYF group, and sulfasalazine group and treated with the corresponding drugs for 28 days. The parameters including body weight, colon length, spleen index, and disease activity index (DAI) and histopathological characteristics were assessed. The myeloperoxidase (MPO) activity and IL-6 level in the colon mucosa were determined with the corresponding commercial kits. The expressions of the Hippo pathway components YAP1, TAZ, P-YAP, and LATS1 were detected in the colon mucosa of each group on different stages by quantitative real-time PCR (qRT-PCR) and western blotting. Immunohistochemical staining was used to evaluate the growth and apoptosis of the colon epithelium. Result. TXYF significantly improved the weight loss, colonic shortening, DAI, spleen enlargement, and histopathological score of the rats with TNBS-induced UC. TXYF also reduced the MPO activity and expression of IL-6 in the colon mucosa. Furthermore, treatment with TXYF significantly increased YAP1 expression in the early stage (3–7 days) and significantly decreased YAP1 expression in the late stage (14–28 days). In the early stage, TXYF inhibited Hippo pathway activity, which promoted proliferation and regeneration of the intestinal mucosa. In the late stage, the Hippo pathway was activated, thereby inhibiting apoptosis and promoting intestinal mucosal differentiation. Conclusion. TXYF alleviated the inflammatory response and promoted mucosal healing in rats with UC, which was probably achieved through the Hippo pathway. These results indicated that TXYF was a potential therapy for treating UC.

Distinct Pattern of Inflammation of Articular Cartilage and the Synovium in Early and Late Hip Femoroacetabular Impingement

2020 ◽  
Vol 48 (10) ◽  
pp. 2481-2488
Author(s):  
Masahiko Haneda ◽  
Muhammad Farooq Rai ◽  
Lei Cai ◽  
Robert H. Brophy ◽  
Regis J. O’Keefe ◽  
...  
Keyword(s):  
Femoroacetabular Impingement ◽  
Late Stage ◽  
Early Stage ◽  
Hip Osteoarthritis ◽  
Cartilage Degeneration ◽  
Control Group ◽  
Acetabular Cartilage ◽  
Similar Expression ◽  
Related Proteins ◽  
Head Neck

Background: The molecular mechanism of how femoroacetabular impingement (FAI) morphology leads to hip osteoarthritis (OA) is yet to be determined. The expression and location of inflammation-related molecules during early- and late-stage FAI have not been previously described. Moreover, the characterization of intra-articular inflammation away from the cam deformity as well as the nature of adjacent synovial tissue have also not been extensively reported. Hypothesis: Early-stage FAI has a similar expression of inflammation-related markers in the head-neck and acetabular cartilage but less synovitis than late-stage FAI. Study Design: Controlled laboratory study. Methods: Head-neck cartilage, acetabular cartilage, and synovial samples were obtained from patients undergoing hip preservation surgery for the treatment of symptomatic cam FAI (early FAI group; n = 15) and advanced OA secondary to cam FAI (late FAI group; n = 15). Samples procured from healthy young adult donors served as the control group (n = 7). Cartilage degeneration was assessed by histology, and the expression of inflammation-related proteins (interleukin–1 beta [IL-1β], matrix metalloproteinase–13 [MMP-13], a disintegrin and metalloproteinase with thrombospondin motifs–4 [ADAMTS-4], type II collagen [COL2], and aggrecan neoepitope [NITEGE]) was measured by immunostaining. Synovial samples in the early and late FAI groups were examined for synovitis and the expression of IL-1β. Results: Head-neck cartilage in the early FAI group showed significantly more degeneration than the control group and an increased expression of inflammation-related proteins (IL-1β: 69.7% ± 18.1% vs 20.2% ± 4.9%, respectively; MMP-13: 79.6% ± 12.6% vs 25.3% ± 9.5%; ADAMTS-4: 83.9% ± 12.2% vs 24.3% ± 11.1%; NITEGE: 89.7% ± 7.7% vs 39.8% ± 20.5%) ( P < .001). Head-neck and acetabular cartilage in the early and late FAI groups showed a similar degree of degeneration. Moreover, a similar expression of inflammation-related proteins was observed between the early and late FAI groups for head-neck cartilage (IL-1β: 69.7% ± 18.1% vs 72.5% ± 13.2%; MMP-13: 79.6% ± 12.6% vs 71.4% ± 18.8%; ADAMTS-4: 83.9% ± 12.2% vs 82.6% ± 12.5%; COL2: 93.6% ± 3.9% vs 92.5% ± 5.8%; NITEGE: 89.7% ± 7.7% vs 95.7% ± 4.7%) and acetabular cartilage (IL-1β: 83.3% ± 24.8% vs 80.7% ± 15.6%; MMP-13: 94.3% ± 9.7% vs 85.2% ± 12.3%; ADAMTS-4: 98.5% ± 2.3% vs 98.4% ± 3.4%; COL2: 99.8% ± 0.7% vs 99.7% ± 1.1%; NITEGE: 96.7% ± 6.7% vs 99.2% ± 2.2%). In contrast, synovitis was minimal with a low expression of IL-1β in the early FAI group compared with the late FAI group. Conclusion: Hip cartilage exhibited an OA phenotype in patients with early-stage FAI, similar to what was observed in hip OA secondary to FAI. Severe synovitis was only evident with late-stage FAI. Clinical Relevance: This study supports the concept that early hip impingement is associated with cartilage degeneration and catabolism.

scholarly journals P039 New molecular markers of the development of ulcerative colitis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S151-S151
Author(s):  
A A Iakovlev ◽  
A Volkov ◽  
G Tarasova ◽  
A Zubova
Keyword(s):  
Ulcerative Colitis ◽  
Molecular Interactions ◽  
Small Heat Shock Protein ◽  
Control Group ◽  
Molecular Characteristics ◽  
Moderate Activity ◽  
Colon Mucosa ◽  
Active Stage ◽  
Functional Features ◽  
Specific Regulation

Abstract Background The mechanisms of ulcerative colitis (UC) progression require detailed study. Modern achievements of proteomic methods of analysis are ideal for research that is free from hypotheses and allows us to define molecular characteristics of inflammation in colon mucosa of UC patients. Methods The study was comparative cohort with parallel design and included 88 patients (range from 22 to 35 years, 37 men and 51 women): 53 (60.2%) pancolitis and 35 (39.8%) left-sided UC, mild and moderate activity. The control group included 30 healthy individuals. Biosamples of colon mucosa in patients with UC in the active stage and in healthy persons were received by ileocolonoscopy with colon mucosa biopsy. The separation of individual proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA). Automated mass spectrometry imaging was performed by MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database. Results We identified following functional groups of peptides and proteins in molecular patterns of colon mucosa in UC patients: SMAD family member 2 (SMAD2) activates the transcription of TFG1β, that leads to specific regulation of the CCN2 gene in cells and the development of fibrosis in colon submucosa in UC patients; the stimulation of the expression of apoС-III in affected colon mucosa in UC is associated with the activation of the FOXO1 signaling pathway that supports inflammatory processes in colon mucosa; the second small heat shock protein (HSP2) controls the apoptosis of colonocytes, is also responsible for the mucosa resistance to therapeutic strategies; caspase 8 protects colonocytes from TNFα-induced cell death through a necroptosis mechanism via the blockade of the RIP3 expression; the expression of prohibitin maintains optimal activity of the electronic transport chain through the activity of transcription factor STAT3 and the decrease in the TNFα expression; significant decrease of the PPARγ expression promotes the activation of STAT and AP-1 signaling pathways, which promotes the activity of immune and inflamation processes in colon mucosa and a significant increase in the NF-kB expression in colon mucosa is associated with the activation of TNFα and IL-1, which promotes the increase of immune processes in colon mucosa. Conclusion Bioinformatics analysis revealed the presence of molecules that are the participants in the universal pathways of UC in the active stage, and the molecular interactions involved. This information may provide new avenues for the development of novel diagnostic tests for UC.

scholarly journals Using random forests to understand unrecognized progression to late-stage CKD, a case-control study

2021 ◽  
Author(s):  
Christopher Hane ◽  
Stephan Dunning ◽  
Jeffrey McPheeters ◽  
David Mosely ◽  
Jennifer St. Clair Russell ◽  
...  
Keyword(s):  
Random Forests ◽  
Late Stage ◽  
Early Stage ◽  
Case Control ◽  
Care Utilization ◽  
Control Group ◽  
Control Analysis ◽  
Fee For Service ◽  
Home Dialysis ◽  
Increased Risk

Abstract Background and objectives Patients with undiagnosed CKD are at increased risk of suboptimal dialysis initiation and therefore reduced access to home dialysis and transplantation as well as poor outcomes. Improved understanding of how patients remain undiagnosed is important to determine better intervention strategies. Design, setting, participants, and measurements A retrospective, matched, case-control analysis of 1,535,053 patients was performed to identify factors differentiating 4 patient types: unrecognized late-stage CKD, recognized late-stage CKD, early-stage CKD and a control group without CKD. The sample included patients with commercial insurance, Medicare Advantage, and Medicare fee-for service coverage. Patient demographics, comorbidities, health care utilization, and prescription use were analyzed using random forests to determine the most salient features discriminating the types. Models were built using all four types, as well as pairwise for each type versus the unrecognized late-stage type. Results Area under the curve for the three pairwise models (unrecognized late-stage vs recognized late-stage; unrecognized late-stage vs early-stage; unrecognized late-stage vs no CKD) were 82%, 68% and 82%. Conclusions The lower performance of the unrecognized late-stage vs early-stage model indicates a greater similarity of these two patient groups. The unrecognized late-stage CKD group is not simply avoiding or unable to get care in a manner distinguishable from the early-stage group. New outreach for CKD to undiagnosed or undetected, insured patients should look more closely at patient sets that are like diagnosed early-stage CKD patients.

scholarly journals The Effect of Bifid Triple Viable on Immune Function of Patients with Ulcerative Colitis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Guohua Li ◽  
Sheng Zeng ◽  
Wangdi Liao ◽  
Nonghua Lv
Keyword(s):  
Ulcerative Colitis ◽  
T Cell ◽  
Immune Function ◽  
Symptom Score ◽  
Peripheral Blood ◽  
Control Group ◽  
Colon Mucosa ◽  
Aminosalicylic Acid ◽  
Significant Difference ◽  
Inflammation Score

Objective. To study effect and its mechanism of Bifid Triple Viable for initially treating ulcerative colitis with 5-aminosalicylic acid.Methods. 82 patients, who were firstly diagnosed as ulcerative colitis, were randomized into experiment group (41 cases, treated with Bifid Triple Viable and Etiasa) and control group (41 cases, treated with Etiasa). The clinic symptom score, colon mucosa inflammation score, and some immune indices were detected and compared between two groups before and two months after treatment.Results. Two months after treatment, the clinical symptom score, colon mucosa inflammation score, and IL-1βexpression in colon mucosa decreased significantly (P<0.01), and IL-10 and IgA expressions in colon mucosa increased significantly (P<0.01). Those differences were more marked in experiment group than control group (P<0.05). However, peripheral blood T cell subgroup, immunoglobulins, and complements had no significant difference between two groups two months after treatment, but the ratio of peripheral blood CD4+ T cell to CD8+ T cell in experiment group increased more than that in control group (P<0.05).Conclusion. Bifid Triple Viable contributed to Etiasa to treat ulcerative colitis in inducing remission period, which was perhaps related to affecting the patient’s immune function.

scholarly journals Study on the effect of Periplaneta americana on ulcerative colitis in rats induced by 2,4,6-trinitrobenzene sulfonic acid

2020 ◽  
Vol 18 ◽  
pp. 205873922094262
Author(s):  
Yi-Hao Che ◽  
Zhi-Bin Yang ◽  
Han-Chao Zhang ◽  
Xiu-Mei Wu ◽  
Min-Zhe Sun ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Sulfonic Acid ◽  
Periplaneta Americana ◽  
Treated Group ◽  
Normal Control Group ◽  
Control Group ◽  
Trinitrobenzene Sulfonic Acid ◽  
Tnf Α ◽  
Ifn Γ ◽  
Tgf Β1

Ulcerative colitis (UC) is a chronic inflammatory disease of intestinal tract, and Periplaneta americana has been found to be effective in the treatment for UC. The purpose of the study was to investigate the therapeutic effect of Periplaneta americana extract Ento-A on UC in rats induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) and to explore its mechanism. The Sprague-Dawley (SD) rats were randomly divided into normal control group; TNBS-treated group; sulfasalazine (SASP) treated group; Ento-A low- (50 mg/kg), medium- (100 mg/kg), and high-dose (200 mg/kg) groups, respectively. The UC model of rats was induced via TNBS. Disease activity index (DAI) was used to evaluate the severity of UC in rats. The macroscopic and microscopic damages of colon were accessed by colon mucosa damage index (CMDI) and histopathological score (HS), respectively. The levels of interleukin-4 (IL-4), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in serum and the contents of myeloperoxidase (MPO), transforming growth factor-β1 (TGF-β1), and epidermal growth factor (EGF) in colonic mucosa were measured by enzyme-linked immunosorbent assay (ELISA). Compared with the normal control group, the TNBS-treated group showed increase in DAI, CMDI, HS, IL-17, TNF-α, IFN-γ as well as MPO and decrease in the levels of IL-4, EGF, and TGF-β1. However, Ento-A-administrated groups reversed the changes in the DAI, CMDI, HS, and the cytokines caused by TNBS. The study indicates that Periplaneta americana extract Ento-A can effectively alleviate the inflammation in TNBS-induced UC of rats, and the mechanism of that may be related to restoring the balance of T helper 1 (Th1)/Th2/Th17/T regulatory (Treg) cytokines.

scholarly journals Regulatory effect of Garidisan on dysbiosis of the gut microbiota in the mouse model of ulcerative colitis induced by dextran sulfate sodium

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ling-yan Pei ◽  
Yu-shi Ke ◽  
Huan-hu Zhao ◽  
Wei-zhi Liu ◽  
Lin Wang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Therapeutic Effect ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Control Group ◽  
Group Model ◽  
Regulatory Effect ◽  
Model Group

Abstract Background Ulcerative colitis (UC) is a modern refractory disease, and its etiology has been difficult to discern. Studies have shown that UC is closely associated with the gut microbiota. Garidisan is composed of wild poppy and Artemisia frigida Willd and is commonly used for the treatment of UC in Inner Mongolia, China. In clinical settings, Garidisan has been found to treat UC effectively, with low recurrence. Previous studies have shown that Garidisan has a good therapeutic effect on mice with UC, but the therapeutic mechanism is still unclear. In this study, we investigated the regulatory effect of Garidisan on dysbiosis of the gut microbiota in a UC mouse model and explored the possible mechanism of the therapeutic effect of Garidisan on UC. Methods The UC mouse model was established by the dextran sulfate sodium (DSS) circulating free water drinking method, and the luminal contents were sampled under sterile conditions. High-throughput sequencing of the 16S rRNA gene V3 + V4 region of the luminal contents of the control group, model group, and Garidisan group was conducted, and clustering of operational taxonomic units (OTUs) and species annotation were performed. The differences in species composition and microbial community structure between individual groups of samples were analyzed using MetaStat, LefSe, rank sum test, and Bayesian causal network analysis. Results The UC mouse model was successfully established and the sequencing results were of adequate quality. There were significant differences in the diversity of luminal contents between the control group, model group, and Garidisan group, and the differences between groups were greater than those within any group. The therapeutic effect of Garidisan on UC is attributed to the direct effect on the Lachnospiraceae family of bacteria. Conclusion Garidisan has a good regulatory effect on the gut microbiota, and Lachnospiraceae could be an important direct target of Garidisan for the treatment of UC.

scholarly journals Evaluation of non-small cell lung cancer treatment strategies in a region of China with low-risk for COVID-19

2020 ◽  
Author(s):  
Minhao Yu ◽  
Yalin Cheng
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Late Stage ◽  
Early Stage ◽  
Treatment Strategies ◽  
Small Cell ◽  
Low Risk ◽  
Control Group ◽  
Small Cell Lung ◽  
Experimental Group

Abstract Purpose This study analyzed the morbidity and mortality associated with non-small cell lung cancer (NSCLC) and evaluated treatment strategies for it in a low-risk area of COVID-19 in China. Materials and methods: We selected patients admitted to Sichuan Science City Hospital from September 2019 to February 2020 and divided them into experimental and control groups. The treatment strategy was evaluated by patients’ prognosis. Results: 9,010 patients were hospitalized. The total morbidity was 0.699%, of which 0.504% was observed in the control group and 0.991% in the experimental group (P=0.024). The total mortality was 0.999/103, of which 0.630/103 was observed in the control group and 1.413/103 in the experimental group (P=0.322). Therapy discontinuation and cancer progression in the experimental group were significantly higher than the control group (P＜0.001, P=0.007). The treatment methods and prognosis were not significantly different for early-stage patients between the two groups. Late-stage patients in the experimental group experienced significantly lower percentages of non-surgical treatments (P＜0.001), higher percentages of discontinued therapies (P＜0.001), lower percentages for prognosis of wellness (P＜0.001), and higher percentages of cancer progression (P＜0.001) than the control group. Conclusion: NSCLC exhibited significantly higher morbidities during the COVID-19 pandemic. The mortality in the experimental group was slightly higher than the control group, while the difference in cancer progression was significant. It is feasible to perform surgery for early-stage NSCLC patients, and treatment should not be suspended for late-stage patients in regions with low-risk for COVID-19 infection.

scholarly journals Protective effects of pterostilbene on ulcerative colitis in rats via suppressing NF-κB pathway and activating PPAR-γ

2019 ◽  
Vol 17 ◽  
pp. 205873921984015
Author(s):  
Liu Shi ◽  
Qing Liu ◽  
Jian-hua Tang ◽  
Jian-jun Wen ◽  
Chen Li
Keyword(s):  
Ulcerative Colitis ◽  
Activity Index ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Group Model ◽  
Protective Effects ◽  
Model Group ◽  
Trinitrobenzenesulfonic Acid ◽  
Ppar Γ ◽  
Tnf Α

Our study aimed to investigate the protective effects and potential mechanisms of pterostilbene on rats with ulcerative colitis (UC). We established 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis rat model. Rats were randomly divided into three groups, including control group, model group, and pterostilbene group (30 mg/kg). Disease activity index (DAI) including body weight, stool consistency, and gross bleeding was measured. The concentration of superoxide dismutases (SODs), glutathione superoxide (GSH-px), malondialdehyde (MDA), and methylpropanediol (MPO) in serum were detected by enzyme-linked immunosorbent assay (ELISA). The levels of interleukin-1 beta (IL-1β), IL-17, IL-6, and tumor necrosis factor–alpha (TNF-α) in serum were also analyzed by ELISA kits. Histological evaluations of colons were conducted. The levels of peroxisome-proliferator-activated receptor–γ (PPAR-γ), nuclear factor-κB (NF-κB), ZO-1, and Occludin were analyzed by immunohistochemistry. Compared with model group, pterostilbene notably suppressed the production of TNF-α, IL-17, IL-1β, IL-6, MDA and MPO in serum, and markedly increased the SOD and GSH-Px activity in serum. Pterostilbene significantly attenuated macroscopic damage and histological injury, when compared with model rats. Furthermore, pterostilbene also markedly activated the expression of PPAR-γ, ZO-1, and Occludin, and suppressed the expression of NF-κB. The protective effects of pterostilbene might be associated with suppression of NF-κB and activation of PPAR-γ. Pterostilbene might be a promising therapeutic agent for colitis treatment.

scholarly journals Gene expression profiles of YAP1, TAZ, CRB3, and VDR in familial and sporadic multiple sclerosis among an Iranian population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sheyda Khalilian ◽  
Zohreh Hojati ◽  
Fariba Dehghanian ◽  
Vahid Shaygannejad ◽  
Seyedeh Zahra Hosseini Imani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Nervous System ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Hippo Pathway ◽  
Gene Expression Profiles ◽  
Control Group ◽  
Sporadic Group ◽  
The Hippo Pathway

AbstractAlterations in the regulatory mechanisms that control the process of myelination in the nervous system, may lead to the impaired myelination in the Multiple sclerosis. The Hippo pathway is an important mediator of myelination in the nervous system and might contribute to the pathophysiology of MS. This study examined via qPCR the RNA expression of YAP1, TAZ, and CRB3 as the key effectors of the Hippo pathway and also, VDR in the peripheral blood of 35 sporadic, 37 familial MS patients; and also 34 healthy first-degree relatives of the familial MS patients (HFR) and 40 healthy individuals without a family history of the disease (control). The results showed the increased expression of VDR in the sporadic group, as compared to other groups. There was also an increased expression of TAZ in the familial and HFR groups, as compared to the control group. The familial and sporadic patients displayed a significantly lower level of expression of YAP1 in comparison to the HFR group. The increased expression level in the sporadic patients and control group, as compared to the HFR group, was seen in CRB3. We also assessed different clinical parameters and MRI characteristics of the patients. Overall, these findings suggest that Hippo pathway effectors and also VDR gene may play a potential role in the pathophysiology of the sporadic and familial forms of MS. Confirmation of different gene expression patterns in sporadic and familial MS groups may have obvious implications for the personalization of therapies in the disease.

scholarly journals De-escalation Antibiotic Therapy Alleviates Organ Injury through Modulation of NET Formation during Sepsis

2020 ◽  
Author(s):  
Tian Xie ◽  
Chengnan Chu ◽  
Shilong Sun ◽  
Xinyu Wang ◽  
Zehua Duan ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Late Stage ◽  
Early Stage ◽  
Neutrophil Extracellular Trap ◽  
Organ Injury ◽  
Control Group ◽  
Histopathological Analysis ◽  
Escalation Therapy ◽  
Significant Difference

Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detail mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular trap (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy based on their effects on NETs formation in CLP model. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. The in vitro study showed that imipenem and ceftriaxone had opposite effects on NETs formation in activated neutrophils. De-escalation therapy resulted in an evaluated MPO-DNA during early stage and decreased MPO-DNA during late stage, which exerted the reverse effects in escalation therapy sepsis animal model. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAseI during early stage of sepsis (p<0.01). Histopathological analysis showed decreased injury in lung, liver and intestine in de-escalation therapy compared with escalation therapy (p<0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p<0.01), however, no significant difference was found between de-escalation and escalation group (p=0.051). We demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage and inhibiting NETs formation in the late stage of sepsis.

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