Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation.
Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-kappaB activation through suppressing IkappaB-alpha degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.
Takeshita
Kei
K
Department of Medicine, School of Medicine, Keio University, Tokyo, Japan.
Suzuki
Yukio
Y
Nishio
Kazumi
K
Takeuchi
Osamu
O
Toda
Kyoko
K
Kudo
Hiroyasu
H
Miyao
Naoki
N
Ishii
Makoto
M
Sato
Nagato
N
Naoki
Katsuhiko
K
Aoki
Takuya
T
Suzuki
Koichi
K
Hiraoka
Rika
R
Yamaguchi
Kazuhiro
K
D000142:Acidosis, Respiratory / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D006935:Hypercapnia / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016177:Macrophage-1 Antigen / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
D039481:CD11b Antigen; D018821:CD18 Antigens; D004731:Endotoxins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1