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 μM) 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)-κB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 μM 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 μM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-κB 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.
Highlights
Acute respiratory distress syndrome (ARDS), which is the most severe form of acute lung injury (ALI), is a critical illness with high mortality
Inflammatory cell recruitment into the alveolar space was evaluated after intratracheal challenge of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 μM) or vehicle (n = 6 for each group) or vehicle
Significant inflammatory cell accumulation into the airspace was observed in the mice that received 10 μM or higher concentration of CpG-ODN
Summary
Acute respiratory distress syndrome (ARDS), which is the most severe form of acute lung injury (ALI), is a critical illness with high mortality. ALI/ARDS may occur in association with direct lung injury, including pneumonia, aspiration of gastric contents, and inhalation of noxious gas, or indirect lung injury, such as sepsis, blood transfusions and shock. Intratracheal administration of endotoxin (lipopolysaccharide; LPS), which is a cell wall component of gramnegative bacteria, has been extensively used as an experimental model of ALI/ARDS following severe pneumonia [2]. The roles of other bacterial components, such as genomic DNA, in the development of lung injury and systemic inflammatory response remain to be determined. The bacterial genome, compared to vertebrate DNA, contains a higher frequency of unmethylated cytosine-phosphate-guanine (CpG) dinucleotides. Small oligodeoxynucleotides (ODN) with unmethylated CpG dinucleotides (CpG-ODN) are able to mimic the immunostimulatory activity of bacterial DNA since bacterial DNA and synthetic ODN share similar base sequences and bind to the same receptor system [3,4,5]
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