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Shock waves increase pulmonary vascular leakage, inflammation, oxidative stress, and apoptosis in a mouse model.

ABSTRACT: Severe lung damage is a major cause of death in blast victims, but the mechanisms of pulmonary blast injury are not well understood. Therefore, it is important to study the injury mechanism of pulmonary blast injury. A model of lung injury induced by blast exposure was established by using a simulation blast device. The effectiveness and reproducibility of the device were investigated. Eighty mice were randomly divided into eight groups: control group and 3 h, 6 h, 12 h, 24 h, 48 h, 7 days and 14 days post blast. The explosive device induced an explosion injury model of a single lung injury in mice. The success rate of the model was as high as 90%, and the degree of lung injury was basically the same under the same pressure. Under the same conditions, the thickness of the aluminum film can be from 0.8 mm to 1.6 mm, and the peak pressure could be from 95.85?±?15.61 PSI to 423.32?±?11.64 PSI. There is no statistical difference in intragroup comparison. A follow-up lung injury experiment using an aluminum film thickness of 1.4 mm showed a pressure of 337.46?±?18.30 PSI induced a mortality rate of approximately 23.2%. Compared with the control group (372?±?23 times/min, 85.9?±?9.4 mmHg, 4.34?±?0.09), blast exposed mice had decreased heart rate (283?±?21 times/min) and blood pressure (73.6?±?3.6 mmHg), and increased lung wet/dry weight ratio(2.67?±?0.11), marked edematous lung tissue, ruptured blood vessels, infiltrating inflammatory cells, increased NF-?B (4.13?±?0.01), TNF-? (4.13?±?0.01), IL-1? (2.43?±?0.01) and IL-6 (4.65?±?0.01) mRNA and protein, decreased IL-10(0.18?±?0.02) mRNA and protein ( P?

SUBMITTER: Tong C

PROVIDER: S-EPMC6108052 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Shock waves increase pulmonary vascular leakage, inflammation, oxidative stress, and apoptosis in a mouse model.

Tong Changci C Liu Yunen Y Zhang Yubiao Y Cong Peifang P Shi Xiuyun X Liu Ying Y Shi Hongxu Jin Lin L Hou Mingxiao M

Experimental biology and medicine (Maywood, N.J.) 20180708 11

Severe lung damage is a major cause of death in blast victims, but the mechanisms of pulmonary blast injury are not well understood. Therefore, it is important to study the injury mechanism of pulmonary blast injury. A model of lung injury induced by blast exposure was established by using a simulation blast device. The effectiveness and reproducibility of the device were investigated. Eighty mice were randomly divided into eight groups: control group and 3 h, 6 h, 12 h, 24 h, 48 h, 7 days and 1 ...[more]

PMID: 29984607

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Project description:Aims:Endothelial hyperpermeability exacerbates multiple organ damage during inflammation or infection. The endothelial glycocalyx, a protective matrix covering the luminal surface of endothelial cells (ECs), undergoes enzymatic shedding during inflammation, contributing to barrier hyperpermeability. A disintegrin and metalloproteinase 15 (ADAM15) is a sheddase capable of cleaving the ectodomains of membrane-bound molecules. Herein, we tested whether and how ADAM15 is involved in glycocalyx shedding and vascular leakage during sepsis. Methods and results:Dextran-150kD exclusion assay revealed lipopolysaccharide (LPS) significantly reduced glycocalyx thickness in mouse cremaster microvessels. Consistently, shedding products of glycocalyx constituents, including CD44 ectodomain, were detected with an increased plasma level after cecal ligation and puncture (CLP)-induced sepsis. The direct effects of CD44 ectodomain on endothelial barrier function were evaluated, which revealed CD44 ectodomain dose-dependently reduced transendothelial electrical resistance (TER) and caused cell-cell adherens junction disorganization. Furthermore, we examined the role of ADAM15 in CD44 cleavage and glycocalyx shedding. An in vitro cleavage assay coupled with liquid chromatography-tandem mass spectrometry confirmed ADAM15 cleaved CD44 at His235-Thr236 bond. In ECs with ADAM15 knockdown, LPS-induced CD44 cleavage and TER reduction were greatly attenuated, whereas, ADAM15 overexpression exacerbated CD44 cleavage and TER response to LPS. Consistently, ADAM15 knockout in mice attenuated CLP-induced increase in plasma CD44. Intravital and electron microscopic images revealed ADAM15 deficiency prevented LPS-induced glycocalyx injury in cremaster and pulmonary microvasculatures. Functionally, ADAM15-/- mice with better-preserved glycocalyx exhibited resistance to LPS-induced vascular leakage, as evidenced by reduced albumin extravasation in pulmonary and mesenteric vessels. Importantly, in intact, functionally vital human lungs, perfusion of LPS induced a significant up-regulation of ADAM15, accompanied by elevated CD44 in the effluent and increased vascular permeability to albumin. Conclusion:Together, our data support the critical role of ADAM15 in mediating vascular barrier dysfunction during inflammation. Its mechanisms of action involve CD44 shedding and endothelial glycocalyx injury.

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Shock waves increase pulmonary vascular leakage, inflammation, oxidative stress, and apoptosis in a mouse model.

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Shock waves increase pulmonary vascular leakage, inflammation, oxidative stress, and apoptosis in a mouse model.

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