ADAR1 is involved in the development of microvascular lung injury.
Deamination of adenosine on pre-mRNA to inosine is a recently discovered process of posttranscription modification of pre-mRNA, termed A-to-I RNA editing, which results in the production of proteins not inherent in the genome. The present study aimed to identify a role for A-to-I RNA editing in the development of microvascular lung injury. To that end, the pulmonary expression and activity of the RNA editase ADAR1 were evaluated in a mouse model of endotoxin (15 mg/kg IP)-induced microvascular lung injury (n=5) as well as in cultured alveolar macrophages stimulated with endotoxin, live bacteria, or interferon. ADAR1 expression and activity were identified in sham lungs that were upregulated in lungs from endotoxin-treated mice (at 2 hours). Expression was localized to polymorphonuclear and monocytic cells. These events preceded the development of pulmonary edema and leukocyte accumulation in lung tissue and followed the local production of interferon-gamma, a known inducer of ADAR1 in other cell systems. ADAR1 was found to be upregulated in alveolar macrophages (MH-S cells) stimulated with endotoxin (1 to 100 microg/mL), live Escherichia coli (5x10(7) colony-forming units), or interferon-gamma (1000 U/mL). Taken together, these data suggest that ADAR1 may play a role in the pathogenesis of microvascular lung injury possibly through induction by interferon.
Rabinovici
R
R
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA. reuven.rabinovici@yale.edu
Kabir
K
K
Chen
M
M
Su
Y
Y
Zhang
D
D
Luo
X
X
Yang
J H
JH
D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins; D004926:Escherichia coli / Q000276:immunology; D017403:In Situ Hybridization; D007288:Inosine / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology; D017393:RNA Editing / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
D004731:Endotoxins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D007288:Inosine; D007371:Interferon-gamma; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine