Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock.
Intestinal barrier dysfunction occurs following hemorrhagic shock and resuscitation (HS/R). High-mobility group B1 (HMGB1) has been shown to increase the permeability of Caco-2 human enterocyte-like epithelial monolayers in vitro. In this study, we found that serum concentrations of HMGB1 were higher in blood samples obtained from 25 trauma victims with hemorrhagic shock than in 9 normal volunteers. We also studied whether treatment with anti-HMGB1 antibody can ameliorate HS/R-induced gut barrier dysfunction in mice. Animals were shocked by withdrawal of blood to maintain mean arterial pressure at 25 to 30 mmHg for 2 h. After resuscitation with shed blood plus Ringer's lactate solution, the mice were treated with either anti-HMGB1 antibody or nonimmune rabbit IgG. Serum HMGB1 concentrations were significantly higher in trauma victims than control mice. Treatment with anti-HMGB1 antibody improved survival at 24 h and ameliorated the development of ileal mucosal hyperpermeability to FITC-labeled dextran. At 24 h after HS/R, treatment with anti-HMGB1 antibody decreased bacterial translocation to mesenteric lymph nodes and was associated with lower circulating concentrations of IL-6 and IL-10. These data support the notion that HMGB1 is a mediator of HS/R-induced gut barrier dysfunction and suggest that anti-HMGB1 antibodies warrant further evaluation as a therapeutic to ameliorate the morbidity of HS/R in trauma patients.
Yang
Runkuan
R
Department of Critical Care Medicine, University of Pittsburgh School of Medicine, PA 15621, USA.
Harada
Tomoyuki
T
Mollen
Kevin P
KP
Prince
Jose M
JM
Levy
Ryan M
RM
Englert
Joshua A
JA
Gallowitsch-Puerta
Margot
M
Yang
LiHong
L
Yang
Huan
H
Tracey
Kevin J
KJ
Harbrecht
Brian G
BG
Billiar
Timothy R
TR
Fink
Mitchell P
MP
D000293:Adolescent; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001794:Blood Pressure; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003911:Dextrans / Q000378:metabolism; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D015600:Glasgow Coma Scale; D024243:HMGB1 Protein / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism*; D007552:Isotonic Solutions / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009573:Nitrites / Q000097:blood; D010539:Permeability / Q000187:drug effects; D012151:Resuscitation; D000077325:Ringer's Lactate; D012771:Shock, Hemorrhagic / Q000503:physiopathology* / Q000628:therapy*; D016019:Survival Analysis; D014947:Wounds and Injuries / Q000503:physiopathology
D000906:Antibodies; D003911:Dextrans; D005456:Fluorescent Dyes; D024243:HMGB1 Protein; D015850:Interleukin-6; D007552:Isotonic Solutions; D009573:Nitrites; D000077325:Ringer's Lactate; D016753:Interleukin-10; D016650:Fluorescein-5-isothiocyanate