Neutrophil Elastase Inhibitor Restores Gut Ischemia Reperfusion-Induced Impairment of Gut Immunity with Reduced Plasma Interleukin-6 Concentrations in Mice

Abstract

Gut-associated lymphoid tissue (GALT) is regarded as central mucosa-associated lymphoid tissue that influences systemic mucosal immunity. Our previous study revealed that gut ischemia and reperfusion (I/R) reduces GALT lymphocyte numbers. Because gut hypoperfusion frequently occurs in trauma, shock, and surgery patients, establishment of a therapeutic method to preserve GALT mass after gut I/R may be important for the prevention of infections. We examined the effects of sivelestat sodium hydrate, a selective inhibitor of neutrophil elastase, on GALT mass and plasma cytokine concentrations in a murine gut I/R model. Seventy male ICR mice were randomized to the control (n = 34) or the sivelestat (n = 36) group. After intravenous cannulation of the animals, the superior mesenteric artery was occluded for 60 min. After reperfusion, physiologic saline or sivelestat 5 mg/kg hourly was infused for 24 h. Sixteen mice in the control and 22 in the sivelestat group were alive at 24 h. Twenty-six mice (n = 13 in each group) were chosen randomly for harvest of the small intestine. Lymphocytes from Peyer patches (PP), the intraepithelial space (IE), and the lamina propria (LP) were counted; and their phenotypes (αβT-cell receptor (TCR), γδTCR, CD4, CD8, B cell) were determined by flow cytometry. Cytokine concentrations (interleukin [IL]-6, IL-1β, IL-10) in the plasma and bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay. Sivelestat treatment did not improve survival but increased PP and IE lymphocyte numbers significantly and reduced the LP CD8(+) cell percentage and plasma IL-6 concentration compared with controls. There were no significant differences between the two groups in other cell phenotypes or cytokine concentrations. Sivelestat treatment after gut I/R may be useful for maintaining gut immunity and preventing systemic inflammatory responses.