MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production.
To clarify the role of the monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) signalling pathway in hyperoxia-induced acute lung injury, CCR2-deficient (CCR2-/-) and wild-type (CCR2+/+) mice were exposed to 85% O(2) for up to 6 days. At day 3, body weight significantly decreased and total protein concentration in bronchoalveolar lavage fluid (BALF) was higher in CCR2-/- mice compared with CCR2+/+ mice. Cumulative survivals were significantly lower in CCR2-/- mice than in CCR2+/+ mice. However, the two groups showed no significant differences in both histological changes and number of macrophages in BALF. Real-time reverse transcriptase-polymerase chain reaction revealed increased mRNA levels of MCP-1, interleukin-1beta thioredoxin-1, and inducible nitric oxide synthase (iNOS) in lung tissues in CCR2-/- mice compared with CCR2+/+ mice. Increased iNOS mRNA levels in alveolar macrophages exposed to 85% O(2) for 48 h in vivo or in vitro were significantly higher in CCR2-/- mice than in CCR2+/+ mice. These results suggest that the MCP-1/CCR2 signalling pathway is protective against hyperoxia-induced tissue injury by suppressing induction of iNOS and consequent production of reactive oxygen species by activated alveolar macrophages.
Okuma
Toshiyuki
T
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Terasaki
Yasuhiro
Y
Sakashita
Naomi
N
Kaikita
Koichi
K
Kobayashi
Hironori
H
Hayasaki
Takanori
T
Kuziel
William A
WA
Baba
Hideo
H
Takeya
Motohiro
M
D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics; D016676:Macrophages, Alveolar / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics
D018932:Chemokine CCL2; D053583:Interleukin-1beta; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D009569:Nitric Oxide; D013879:Thioredoxins; D052247:Nitric Oxide Synthase Type II