title: Intratracheal synthetic CpG oligodeoxynucleotide causes acute lung injury with systemic inflammatory response.
abstract: Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG) motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN) with unmethylated CpG dinucleotides (CpG-ODN) are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 microM) or control ODN without CpG motif. Bronchoalveolar lavage (BAL) fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF)-kappaB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 microM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 microM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-kappaB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered.
authors.affiliation: Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan. tasaka@cpnet.med.keio.ac.jp
authors.forename: Sadatomo
authors.initials: S
authors.lastname: Tasaka
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kamata
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakano
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shinoda
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kimizuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Seitaro
authors.initials: S
authors.lastname: Fujishima
authors.forename: Taku
authors.initials: T
authors.lastname: Miyasho
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000187:drug effects*; D055370:Lung Injury / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000009:adverse effects*; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics*; D014132:Trachea
chemical_list: D009838:Oligodeoxyribonucleotides