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Herpes Virus Entry Mediator (HVEM) Expression Promotes Inflammation/ Organ Injury in Response to Experimental Indirect-Acute Lung Injury

Cheng, Tingting*; Bai, Jianwen; Chung, Chun-Shiang; Chen, Yaping; Fallon, Eleanor A.; Ayala, Alfred

doi: 10.1097/SHK.0000000000001174
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ABSTRACT Therapeutic interventions to treat acute lung injury (ALI) remain largely limited to lung-protective strategies, as a real molecular pathophysiologically driven therapeutic intervention has yet to become available. While we have previously documented the expression of herpes virus entry mediator (HVEM) on leukocytes of septic mice and critically ill patients, its functional role in shock/sepsis-induced ALI has not yet been studied. Inasmuch, a murine model of indirect ALI (iALI) was induced by hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), septic challenge and HVEM-siRNA or phosphate buffered saline was administrated by intratracheal instillation 2 h after hemorrhage to determine the role of HVEM in the development of experimental iALI. Indices of lung injury were measured. HVEM expression was significantly elevated in iALI mice. Compared with phosphate buffered saline treated iALI mice, HVEM knock-down by siRNA caused a reduction of cytokine/chemokine levels, myeloperoxidase activity, broncho-alveolar lavage fluid (BALF) cell count and protein concentration. HVEM-siRNA treatment reduced inflammation and attenuated pulmonary architecture destruction as well as provided an early (60 h post HEM-CLP) survival benefit in iALI mice. This ability of anti-HVEM treatment to prevent the development of iALI and provide a transient survival benefit implies that mitigating signaling through HVEM may be a novel target worth further investigation.

*Department of Respiratory Internal Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

Department of Emergency Internal Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

Division of Surgical Research/Department of Surgery, Lifespan-Rhode Island Hospital and Brown University, Providence, Rhode Island

Address reprint requests to Alfred Ayala, PhD, Professor of Surgery, Division of Surgical Research, Aldrich 227, Rhode Island Hospital/the Alpert School of Medicine at Brown University, 593 Eddy Street, Providence, RI 02903. E-mail: aayala@lifespan.org

Received 12 March, 2018

Revised 29 March, 2018

Accepted 27 April, 2018

TC and JB contributed equally to this work.

This work was supported by the following grants: R35 GM118097 (AA) from the National Institutes of Health/National Institute of General Medical Sciences as well as “Armand D. Versaci” fellowship (EAF).

The authors report no conflicts of interest.

© 2019 by the Shock Society