High mobility group box 1 as a mediator of endotoxin administration after hemorrhagic shock-primed lung injury.
High mobility group box 1 (HMGB1) was discovered as a novel late-acting cytokine that contributes to acute lung injury (ALI). However, the contribution of HMGB1 to two-hit-induced ALI has not been investigated. To examine the participation of HMGB1 in the pathogenesis of ALI caused by the two-hit hypothesis, endotoxin was injected intratracheally in a hemorrhagic shock-primed ALI mouse model. Concentrations of HMGB1 in the lung of the shock group were markedly increased at 16 h (1.63 +/- 0.05, compared to the control group: 1.02 +/- 0.03; P < 0.05), with the highest concentration being observed at 24 h. In the sham/lipopolysaccharide group, lung HMGB1 concentrations were found to be markedly increased at 24 h (1.98 +/- 0.08, compared to the control group: 1.07 +/- 0.03; P < 0.05). Administration of lipopolysaccharide to the hemorrhagic shock group resulted in a notable HMGB1 increase by 4 h, with a further increase by 16 h. Intratracheal lipopolysaccharide injection after hemorrhagic shock resulted in the highest lung leak at 16 h (2.68 +/- 0.08, compared to the control group: 1.05 +/- 0.04; P < 0.05). Compared to the hemorrhagic shock/lipopolysaccharide mice, blockade of HMGB1 at the same time as lipopolysaccharide injection prevented significantly pulmonary tumor necrosis factor-alpha, interleukin-1beta and myeloperoxidase. Lung leak was also markedly reduced at 16 h; blockade of HMGB1 24 h after lipopolysaccharide injection failed to alter lung leak or myeloperoxidase at 48 h. Our observations suggest that HMGB1 plays a key role as a late mediator when lipopolysaccharide is injected after hemorrhagic shock-primed ALI and the kinetics of its release differs from that of one-hit ALI. The therapeutic window to suppress HMGB1 activity should not be delayed to 24 h after the disease onset.
Guo
F
F
Department of Respiratory Diseases, Nanjing University, Nanjing General Hospital of Nanjing Military Command, Jiagsu, China.
Shi
Y
Y
Xu
H
H
Ding
J
J
D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D015153:Blotting, Western; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012771:Shock, Hemorrhagic / Q000378:metabolism*
D000906:Antibodies; D004731:Endotoxins; D024243:HMGB1 Protein; D018836:Inflammation Mediators