HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis-induced acute lung injury.
OBJECTIVE
Circulating levels of the proinflammatory mediator High Mobility Group Box Protein 1 (HMGB1) are increased in septic patients and may contribute to sepsis-induced organ dysfunction. Although HMGB1 has been shown to activate neutrophils from healthy volunteers, the responses of neutrophils from septic patients to HMGB1 have not been reported. In the present study we evaluated gene expression and activation of major intracellular signaling pathways in peripheral blood neutrophils obtained from patients with sepsis-induced acute lung injury after culture with HMGB1 or LPS.


METHODS
Ex-vivo study performed in neutrophils from patients with sepsis-induced acute lung injury.


METHODS
Immunology and genetics laboratory at an academic medical center.


METHODS
Twenty-two adult patients with sepsis-induced acute lung injury.


RESULTS
Using gene arrays, distinct patterns of gene expression were found in neutrophils from septic patients after stimulation with HMGB1 or LPS. While more than three-quarters of the genes upregulated by HMGB1 in neutrophils from septic patients also demonstrated increased expression after culture with LPS, the majority of genes affected by LPS did not show altered expression in neutrophils stimulated with HMGB1. Culture of neutrophils with HMGB1 induced downregulation of its own expression, a finding not present after exposure to LPS. Although HMGB1 and LPS both increased nuclear translocation of NF-kappaB, the magnitude of this effect was greater in LPS stimulated neutrophils from patients with sepsis-induced acute lung injury.


CONCLUSIONS
These findings demonstrate that the patterns of gene expression differ between neutrophils from septic patients stimulated with HMGB1 or LPS, and also that neutrophils from septic patients are not anergic but instead demonstrate intact activation of NF-kappaB after exposure to LPS or HMGB1.
Silva
Eliezer
E
Intensive Care Unit, Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil.
Arcaroli
John
J
He
Qianbin
Q
Svetkauskaite
Daiva
D
Coldren
Christopher
C
Nick
Jerry A
JA
Poch
Katie
K
Park
Jong Sung
JS
Banerjee
Anirban
A
Abraham
Edward
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D018805:Sepsis / Q000150:complications*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases