Alpha-chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis.
High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of alpha-chemokine receptors in the HMGB1-induced inflammatory injury and show that alpha-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the alpha-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of alpha-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 microg) directly into the lungs and administered a subcutaneous alpha-chemokine receptor inhibitor, Antileukinate (200 microg). alpha-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 +/- 3.2 vs. 8.1 +/- 2.4 x 10(4) cells; total protein: 120 +/- 48 vs. 311 +/- 129 microg/ml; reactive nitrogen species: 2.3 +/- 0.3 vs. 3.5 +/- 1.3 microM; and macrophage migration inhibitory factor: 6.4 +/- 4.2 vs. 37.4 +/- 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are alpha-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that alpha-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.
Lin
Xinchun
X
Department of Surgery, North Shore University Hospital, Long Island Jewish Medical Center, Manhasset, NY 11030, USA.
Yang
Huan
H
Sakuragi
Tohru
T
Hu
Maowen
M
Mantell
Lin L
LL
Hayashi
Shinichiro
S
Al-Abed
Yousef
Y
Tracey
Kevin J
KJ
Ulloa
Luis
L
Miller
Edmund J
EJ
D000818:Animals; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality
D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C404915:Cxcl2 protein, mouse; D024243:HMGB1 Protein; D009842:Oligopeptides; D019707:Receptors, Chemokine; C118980:antileukinate