-Original-

Intravenous Immunoglobulin Attenuates Cecum Ligation and Puncture-Induced Acute Lung Injury by Inhibiting Apoptosis of Alveolar Epithelial Cells

Jun Hagiwara¹, Marina Yamada², Norio Motoda³ and Hiroyuki Yokota¹

¹Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
²Faculty of Medical Science, Nippon Sport Science University, Kanagawa, Japan
³Department of Pathology, Nippon Medical School Musashi Kosugi Hospital, Kanagawa, Japan

Purpose: Intravenous immunoglobulin (IVIG) therapy has been used to treat sepsis, but its mechanisms of action remain unclear. Sepsis causes multiple organ failure, such as acute lung injury (ALI), which involves apoptosis of alveolar epithelial cells. In this study, we hypothesized that IVIG suppresses apoptosis in alveolar epithelial cells and evaluated mortality, cytokine levels, histological changes in the lung, and alveolar epithelial cell apoptosis after IVIG administration, in mice with experimentally induced sepsis.
Methods: Mice received an injection of vehicle (saline) or immunoglobulin (100 mg/kg or 400 mg/kg) into the tail vein, after which they underwent cecal ligation and puncture. A sham-operated group was used as the normal control. Survival was assessed in all groups after 72 hours. Plasma levels of TNF-α and IL-6, histopathological changes and wet-to-dry ratio in lung, and alveolar epithelial cell apoptosis were evaluated in all groups at 4 hours after surgery.
Results: In the vehicle group, histopathological injury of the lung was severe, and apoptosis of alveolar epithelial cells was significant. Survival and plasma cytokine levels were better in the IVIG treatment groups than in the vehicle group. IVIG 400 mg/kg suppressed apoptosis of alveolar epithelial cells and reduced ALI.
Conclusion: IVIG suppressed inflammatory cytokine levels and improved survival. Lung histopathology and alveolar epithelial cell apoptosis were improved by IVIG treatment, in a dose-dependent manner. Suppressing apoptosis in alveolar epithelial cells appears to be a mechanism by which IVIG improves survival.

J Nippon Med Sch 2020; 87: 129-137

Keywords
sepsis, intravenous immunoglobulin, animal, apoptosis of alveolar epithelial cells

Correspondence to
Jun Hagiwara, MD, Department of Emergency and Critical Care Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
jun-nms@pop21.odn.ne.jp

Received, October 18, 2019
Accepted, November 14, 2019