Neutrophil elastase inhibitor restores gut ischemia reperfusion-induced impairment of gut immunity with reduced plasma interleukin-6 concentrations in mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Sivelestat treatment after gut I/R may be useful for maintaining gut immunity and preventing systemic inflammatory responses.
Surgical Center, The University of Tokyo, Tokyo, Japan. fukatsu-1su@h.u-tokyo.ac.jp
Kazuhiko
K
Fukatsu
Kazuya
K
Tanabe
Yoshinori
Y
Maeshima
Jiro
J
Omata
Hiroshi
H
Yasuhara
Daizoh
D
Saitoh
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000276:immunology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007511:Ischemia / Q000276:immunology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015424:Reperfusion; D013449:Sulfonamides / Q000627:therapeutic use*; D016019:Survival Analysis
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine