Dataset Information

Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx.

ABSTRACT: Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20?mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48?hours after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12?hours after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2?mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12?hours after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxemia. Inhibition of NE may be a useful tool for the management of endotoxemia.

SUBMITTER: Fukuta T

PROVIDER: S-EPMC7748054 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx.

Fukuta Tetsuya T Okada Hideshi H Takemura Genzou G Suzuki Kodai K Takada Chihiro C Tomita Hiroyuki H Suzuki Akio A Oda Kazumasa K Uchida Akihiro A Matsuo Saori S Fukuda Hirotsugu H Yano Hirohisa H Muraki Isamu I Zaikokuji Ryogen R Kuroda Ayumi A Nishio Ayane A Sampei So S Miyazaki Nagisa N Hotta Yasuaki Y Yamada Noriaki N Watanabe Takatomo T Morishita Kentaro K Doi Tomoaki T Yoshida Takahiro T Ushikoshi Hiroaki H Yoshida Shozo S Maekawa Yoichi Y Ogura Shinji S

Shock (Augusta, Ga.) 20200901 3

Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, an ...[more]

PMID: 31764619

Similar Datasets

Project description:IntroductionMyocardial dysfunction occurs in patients with sepsis due to vascular endothelial injury. Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries through endothelial glycocalyx (eGC) protection.HypothesisWe hypothesized that rhTM attenuates myocardial dysfunction via the inhibition of vascular endothelial injury during sepsis.MethodsTen-week-old male C57BL6 mice were injected intraperitoneally with 20 mg/kg of lipopolysaccharide (LPS). In rhTM-treated mice, rhTM was injected intraperitoneally at 3 and 24 h after LPS injection. Saline was injected intraperitoneally as control. To assess for eGC injury, intensity score was measured 48 h after the LPS injection. To confirm vascular endothelial injuries, ultrastructural analysis was performed using scanning (SEM) and transmission electron microscopy (TEM).ResultsThe survival rate of the rhTM group at 48 h after LPS injection was significantly higher than that of the control group (68% vs. 17%, p < 0.05). The serum level of troponin I in the rhTM group was lower than that in the control (2.2 ± 0.4 ng/dL vs 9.4 ± 1.1 ng/dL, p < 0.05). The expression of interleukin-6 (IL-6) was attenuated in the rhTM-treated group than in the control (65.3 ± 15.3 ng/mL vs 226.3 ± 19.4 ng/mL, p < 0.05). The serum concentration of syndecan-1, a marker of glycocalyx damage, was significantly decreased 48 h post-administration of LPS in the rhTM-treated group than in the control group. In ultrastructural analysis using SEM and TEM, eGC peeled off from the surface of the capillary lumen in the control. Conversely, the eGC injury was attenuated in the rhTM group. Gene set enrichment analysis revealed that osteomodulin, osteoglycin proline/arginine-rich end leucine-rich repeat protein, and glypican-1, which are proteoglycans, were preserved by rhTM treatment. Their protein expression was retained in endothelial cells.ConclusionrhTM attenuates sepsis-induced myocardial dysfunction via eGC protection.

Dataset Information

Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx.

Publications

Neutrophil Elastase Inhibition Ameliorates Endotoxin-induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets