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Lung Protective Effects of Low-Volume Resuscitation and Pharmacologic Treatment of Swine Subjected to Polytrauma and Hemorrhagic Shock

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Abstract

Hemorrhage is a common cause of death in the battlefield. Valproic acid (VPA) has been associated with improved outcomes in multiple models of trauma, when combined with isotonic fluid resuscitation. However, isotonic fluid administered in this setting is logistically impractical and may be associated with complications. In this study, we sought to evaluate the feasibility and immunologic impact of combining VPA treatment with low-volume hypertonic saline (HTS). In vivo: female Yorkshire swine were subjected to hemorrhage (40% total blood volume) and polytrauma (rib fracture and delayed liver injury). Animals were kept in shock for 30 minutes and resuscitated with (1) normal saline (NS, 3× hemorrhaged volume), (2) HTS (7.5% saline, 4 mL/kg), or (3) HTS + VPA (4 mg/kg; 150 mg/kg; n = 3/cohort). After 18 hours of observation, animals were euthanized and the lungs evaluated for acute injury and expression of myeloperoxidase (MPO) and caveolin-1 (Cav-1). In vitro: human umbilical vein endothelial cells (HUVECs) were exposed to anoxic conditions (5% CO2, 95% N2) for 16 hours in (1) normosmotic, (2) hyperosmotic (400 mOsm), or (3) hyperosmotic + VPA (4 mM) media. Immunohistochemistry and Western blots were performed to determine Cav-1 expression. Lungs from VPA-treated animals demonstrated decreased acute injury, MPO expression, and endothelial expression of Cav-1 when compared to lungs from animals resuscitated with NS or HTS alone. Similarly, HUVECs cultured in hyperosmotic media containing VPA demonstrated decreased expression of Cav-1. This study demonstrates that combined treatment with VPA and HTS is a viable strategy in hemorrhagic shock and polytrauma. Attenuation of lung injury following VPA treatment may be related to modulation of the inflammatory response.

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Acknowledgements

This work was funded by a grant from Department of Defense W81XWH-09-2-0001to YL. Designed study: HBA, YL; performed research: BP, XD, BL; collected data: BP, TM, MJD; analyzed data: BP, PEG, XD; wrote paper: VCN, BP, ISD; revised manuscript: VCN, BP, XW, YL.

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    Authors and Affiliations

    1. Department of Surgery, University of Michigan Health System, NCRC Building 26 Room 363N, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA

      Vahagn C. Nikolian, Baihong Pan, Isabel S. Dennahy, Patrick E. Georgoff, Baoling Liu, Hasan B. Alam & Yongqing Li

    2. Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

      Baihong Pan

    3. Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

      Tomaz Mesar & Michael J. Duggan

    4. Department of Pathology, Loyola University Medical Center, Maywood, IL, USA

      Xiuzhen Duan

    5. Emergency Department, The First Hospital of China Medical University, Shenyang, China

      Xizi Wu

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    1. Vahagn C. Nikolian
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    Correspondence to Yongqing Li.

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    This research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating experiments involving animals. The study adhered to the principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, and was approved by the Institutional Animal Care and Use Committee at Massachusetts General Hospital. All procedures were performed under the supervision of a veterinarian.

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    The authors declare that they have no conflict of interest.

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    Vahagn C. Nikolian and Baihong Pan contributed equally to project and manuscript. Co-first authorship.

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    S1 Fig

    VPA decreased anoxia-induced expression of Caveolin-1 (Cav-1) in HUVECs. A, Microscopic images of HUVECs in 100 mm culture dishes; B, Representative immunoblots of Cav-1 in HUVECs cell extract and actin as an internal control of protein-loading; C, Cav-1 protein bands quantified by densitometry and normalized with actin were expressed as mean values ± SD (n = 4/group); *, p ≤ 0.0015 compared to sham group; #, P ≤ 0.001 compared to Anoxia + HTS + VPA group; NS, normal saline; HTS, hypertonic saline; VPA, valproic acid; Sham, no trauma and hemorrhagic shock, no treatment. (GIF 102 kb)

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    Nikolian, V.C., Pan, B., Mesar, T. et al. Lung Protective Effects of Low-Volume Resuscitation and Pharmacologic Treatment of Swine Subjected to Polytrauma and Hemorrhagic Shock. Inflammation 40, 1264–1274 (2017). https://doi.org/10.1007/s10753-017-0569-6

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