MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production

• Published in: International journal of experimental pathology Vol. 87; no. 6; pp. 475 - 483
• Main Authors: Okuma, Toshiyuki, Terasaki, Yasuhiro, Sakashita, Naomi, Kaikita, Koichi, Kobayashi, Hironori, Hayasaki, Takanori, Kuziel, William A., Baba, Hideo, Takeya, Motohiro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2006; Blackwell Science; Blackwell Science Inc
• Subjects: Acute Disease; Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; CCR2; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; hyperoxia; Hyperoxia - metabolism; inducible nitric oxide synthase; Interleukin-1beta - genetics; Investigative techniques, diagnostic techniques (general aspects); macrophages; Macrophages, Alveolar - enzymology; Medical sciences; Mice; Mice, Knockout; Models, Animal; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - genetics; Original; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; reactive oxygen species; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; Respiratory Distress Syndrome, Adult - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Signal Transduction; Thioredoxins - genetics; Lung disease; Oxygen; Respiratory disease; Enzyme; Acute; CCR2 chemokine receptor; Chemokine receptor; reactive oxygen spe cies; CC chemokine; Nitric-oxide synthase; inducible nitric oxide synthase; Anatomic pathology; Regulation(control); macrophages; Signaling pathway; Nitric oxide; Hyperoxia; Production; Oxidoreductases; Macrophage; CCR2
• ISSN: 0959-9673; 1365-2613
• DOI: 10.1111/j.1365-2613.2006.00502.x

Summary
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% O2 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‐1β 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% O2 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.