更新于：2024-11-01

Endotoxin Hyporesponsiveness

内毒素低反应性

更新于：2024-11-01

基本信息

别名

简介-

关联

项与内毒素低反应性相关的药物

Doramapimod

达马莫德

靶点

p38 MAPK

作用机制

p38 MAPK抑制剂

在研机构

RespiVert Ltd.

原研机构

C.H. Boehringer Sohn AG & Co. KG

在研适应症-

非在研适应症

克罗恩病 [+5]

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与内毒素低反应性相关的临床试验

NCT02211170 / Completed临床1期

The Effect of Single Oral Dose BIRB 796 BS (50 and 600 mg) on Endotoxin-induced Inflammatory Responses in Healthy Human Subjects. A Placebo-controlled, Randomised, Parallel, Double-blinded Study.

Study to determine the effect of a single dose BIRB 796 BS on systemic inflammatory responses induced by endotoxin in healthy humans

开始日期2000-02-01

申办/合作机构

Boehringer Ingelheim GmbH

100 项与内毒素低反应性相关的临床结果

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100 项与内毒素低反应性相关的转化医学

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0 项与内毒素低反应性相关的专利（医药）

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301

项与内毒素低反应性相关的文献（医药）

2024-10-01·Cannabis and Cannabinoid Research

Cannabidiol Reduces Systemic Immune Activation in Experimental Acute Lung Injury

Article

作者: Kelly, Melanie ; Hall, Stefan ; Lehmann, Christian ; Faridi, Sufyan ; Trivedi, Purvi ; Zhou, Juan ; Castonguay, Mathieu

Background: The underlying pathomechanism of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is the immune response to inflammation or infection within the pulmonary microcirculation. Systemic spread of pathogens, activated immune cells, and inflammatory mediators contributes significantly to mortality in patients with ARDS. Objective: The endogenous cannabinoid system is a major modulator of the immune response during inflammation and infection. Phytocannabinoids, such as cannabidiol (CBD), have shown promising anti-inflammatory effects in several pathologies. The overall objective of this study was to evaluate the effects of CBD on local and systemic inflammation in endotoxin-induced ALI in mice. Materials and Methods: ALI was induced by pulmonary endotoxin challenge. Four groups of male C57BL/6 mice were randomized in this study: control, ALI, ALI with CBD treatment, and control with CBD treatment. Analyses of local and systemic cytokine levels, lung histology, and leukocyte activation as visualized by intravital microscopy of the intestinal and pulmonary microcirculation were performed 6 h following intranasal endotoxin administration. Results: Pulmonary endotoxin challenge induced significant inflammation evidenced by local and systemic cytokine and chemokine release, lung histopathology, and leukocyte adhesion. Intraperitoneal CBD treatment resulted in a significant decrease in systemic inflammation as shown by reduced leukocyte adhesion in the intestinal microcirculation and reduced plasma cytokine and chemokine levels. Pulmonary chemokine levels were decreased, while pulmonary cytokine levels were unchanged. Surprisingly, the ALI score was slightly increased by CBD treatment in a manner driven by enhanced neutrophil infiltration of the alveoli. Conclusion: In this model of experimental ALI, CBD administration was associated with reduced systemic inflammation and heterogeneous effects on pulmonary inflammation. Future studies should explore the mechanisms involved as they relate to neutrophil infiltration and proinflammatory mediator production within the lungs.

2024-04-01·Zhonghua wei zhong bing ji jiu yi xue

[Nuclear factor E2-related factor 2 attenuates endotoxin-induced acute lung injury by up-regulating cellular tight junction protein Claudin-18 expression].

Article

作者: Gao, Qiaoying ; Liu, Huayang ; Yu, Jianbo ; Shi, Jia ; Liu, Shasha ; Dong, Shu'an

OBJECTIVETo investigate the effect of nuclear factor E2-related factor 2 (Nrf2) on the cellular tight junction protein Claudin-18 in endotoxin-induced acute lung injury (ALI).METHODSEighteen healthy male C57BL/6 mice were divided into control group, endotoxin-induced ALI model group (ALI group) and Nrf2 activator tert-butylhydroquinone (tBHQ) pretreatment group (tBHQ+ALI group) according to random number table method, with 6 mice in each group. Mice endotoxin-induced ALI model was reproduced by intraperitoneal injection of lipopolysaccharide (LPS, 15 mg/kg), and the mice in the control group was injected with an equal amount of phosphate buffer solution (PBS). The mice in the tBHQ+ALI group received three intraperitoneal injections of tBHQ (a total of 50 mg/kg) at an interval of 1 hour before molding. The last injection of tBHQ was accompanied by LPS of 15 mg/kg. The mice in the control group and model group were given equal amounts of PBS, and PBS or LPS was given at the last injection. The mice were sacrificed at 12 hours after LPS injection to take lung tissues. After the lung tissue was stained with hematoxylin-eosin (HE) staining, the pathological changes were observed under light microscopy, and the lung injury score was calculated. The lung wet/dry ratio (W/D) was determined. Nrf2 protein expression in the lung tissue was detected by Western blotting. Positive expression of Claudin-18 in the lung tissue was determined by immunohistochemistry.RESULTSThe lung tissue showed normal structure, without significant pathological change in the control group. Compared with the control group, the alveolar septum widened accompanied by inflammatory cell infiltration, capillary hyperemia and tissue edema in the ALI group, the lung injury score and lung W/D ratio were significantly increased (lung injury score: 6.50±1.05 vs. 1.83±0.75, lung W/D ratio: 3.79±0.22 vs. 3.20±0.14, both P < 0.01), and the Nrf2 protein expression and Claudin-18 positive expression in the lung tissue were significantly lowered [Nrf2 protein (Nrf2/β-actin): 0.41±0.33 vs. 1.22±0.33, Claudin-18 (A value): 0.28±0.07 vs. 0.44±0.10, both P < 0.05]. After tBHQ pretreatment, the degree of lung histopathological injury was significantly reduced compared with the ALI group, the alveolar space slightly abnormal, inflammatory cell infiltration and tissue edema reduced, the lung injury score and lung W/D ratio were significantly decreased (lung injury score: 3.00±0.89 vs. 6.50±1.05, lung W/D ratio: 3.28±0.19 vs. 3.79±0.22, both P < 0.01), and Nrf2 protein expression and Claudin-18 positive expression in the lung tissue were significantly increased [Nrf2 protein (Nrf2/β-actin): 1.26±0.09 vs. 0.41±0.33, Claudin-18 (A valure): 0.45±0.04 vs. 0.28±0.07, both P < 0.05].CONCLUSIONSNrf2 alleviated pulmonary edema and improved endotoxin-induced ALI by up-regulating Claudin-18 expression.

2023-08-01·Free Radical Biology and Medicine

Ginsenoside Rg1 protects cardiac mitochondrial function via targeting GSTP1 to block S-glutathionylation of optic atrophy 1

Article

作者: Zhu, Huimin ; Yao, Peng ; Yan, Changyang ; Yang, Hua ; Li, Yi ; Li, Ping

Mitochondrial dysfunction is a fundamental challenge in myocardial injury. Ginsenoside Rg1 (Rg1) is a bioactive compound with pharmacological potential for cardiac protection. Optic atrophy 1 (OPA1) acts as a mitochondrial inner membrane protein that contributes to the structural integrity and function of mitochondria. This study investigated the protective role of Rg1 in septic cardiac injury from the perspective of OPA1 stability. Rg1 protected cardiac contractive function against endotoxin injury in mice by maintaining mitochondrial cristae structure. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial fragmentation and destruction of mitochondrial biogenesis, which were prevented by Rg1, possibly due to the preservation of the integrity of cristae structure. In support, the beneficial effects of Rg1 on cardioprotection and mitochondrial biogenesis were diminished by OPA1 deficiency subjected to the LPS challenge. Mechanistically, LPS stimulation triggered intracellular glutathione destabilization that promoted S-glutathionylation of OPA1 at Cys551, leading to the dissociation of OPA1-Mitofilin. Rg1 interacted with Glutathione S-transferase pi (GSTP1) to inhibit its mediated S-glutathionylation of OPA1, thereby promoting OPA1-Mitofilin interaction and protecting mitochondrial cristae structure. These findings suggest that GSTP1/OPA1 axis may be a beneficial strategy for the treatment of myocardial injury, and expand the clinical application of Rg1.