Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis.
Flagellin is a recently identified bacterial product that elicits immune response via toll-like receptor 5. Here, we demonstrate that flagellin is an extraordinarily potent proinflammatory stimulus in the lung during sepsis. In vitro, flagellin triggers the production of interleukin (IL)-8 by human lung epithelial (A549) cells, with 50% of the maximal response obtained at a concentration of 2 x 10(-14) M. Flagellin also induces the expression of ICAM-1 in vitro. Intravenous administration of flagellin to mice elicited a severe acute lung inflammation that was significantly more pronounced than following lipopolysaccharide (LPS) administration. Flagellin induced a local release of proinflammatory cytokines, the accumulation of inflammatory cells, and the development of pulmonary hyperpermeability. These effects were associated with the nuclear translocation of the transcription NF-kappaB in the lung. Flagellin remained active in inducing pulmonary inflammation at doses as low as 10 ng/mouse. In the plasma of patients with sepsis, flagellin levels amounted to 7.1 +/- 0.1 ng/mL. Plasma flagellin levels showed a significant positive correlation with the lung injury score, with the alveolar-arterial oxygen difference as well as with the duration of the sepsis. Flagellin emerges as a potent trigger of acute respiratory complications in gram-negative bacterial sepsis.
Liaudet
Lucas
L
Inotek Pharmaceuticals Corporation, Beverly, MA 01915, USA.
Szabó
Csaba
C
Evgenov
Oleg V
OV
Murthy
Kanneganti G
KG
Pacher
Pál
P
Virág
László
L
Mabley
Jon G
JG
Marton
Anita
A
Soriano
Francisco G
FG
Kirov
Mikhail Y
MY
Bjertnaes
Lars J
LJ
Salzman
Andrew L
AL
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002478:Cells, Cultured; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005408:Flagellin / Q000097:blood / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology; D007375:Interleukin-1 / Q000097:blood; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000097:blood; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D012475:Salmonella / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D016328:NF-kappa B; D005408:Flagellin; D009569:Nitric Oxide