Effects of intratracheal administration of nuclear factor-kappaB decoy oligodeoxynucleotides on long-term cigarette smoke-induced lung inflammation and pathology in mice.
To determine if nuclear factor-kappaB (NF-kappaB) activation may be a key factor in lung inflammation and respiratory dysfunction, we investigated whether NF-kappaB can be blocked by intratracheal administration of NF-kappaB decoy oligodeoxynucleotides (ODNs), and whether decoy ODN-mediated NF-kappaB inhibition can prevent smoke-induced lung inflammation, respiratory dysfunction, and improve pathological alteration in the small airways and lung parenchyma in the long-term smoke-induced mouse model system. We also detected changes in transcriptional factors. In vivo, the transfection efficiency of NF-kappaB decoy ODNs to alveolar macrophages in BALF was measured by fluorescein isothiocyanate (FITC)-labeled NF-kappaB decoy ODNs and flow cytometry post intratracheal ODN administration. Pulmonary function was measured by pressure sensors, and pathological changes were assessed using histology and the pathological Mias software. NF-kappaB and activator protein 1(AP-1) activity was detected by the electrophoretic motility shift assay (EMSA). Mouse cytokine and chemokine pulmonary expression profiles were investigated by enzyme-linked immunosorbent assay (ELISA) in bronchoalveolar lavage fluid (BALF) and lung tissue homogenates, respectively, after repeated exposure to cigarette smoke. After 24 h, the percentage of transfected alveolar macrophages was 30.00 +/- 3.30%. Analysis of respiratory function indicated that transfection of NF-kappaB decoy ODNs significantly impacted peak expiratory flow (PEF), and bronchoalveolar lavage cytology displayed evidence of decreased macrophage infiltration in airways compared to normal saline-treated or scramble NF-kappaB decoy ODNs smoke exposed mice. NF-kappaB decoy ODNs inhibited significantly level of macrophage inflammatory protein (MIP) 1alpha and monocyte chemoattractant protein 1(MCP-1) in lung homogenates compared to normal saline-treated smoke exposed mice. In contrast, these NF-kappaB decoy ODNs-treated mice showed significant increase in the level of tumor necrosis factor-alpha(TNF-alpha) and pro-MMP-9(pro-matrix metalloproteinase-9) in mice BALF. Further measurement revealed administration of NF-kappaB decoy ODNs did not prevent pathological changes. These findings indicate that NF-kappaB activation play an important role on the recruitment of macrophages and pulmonary dysfunction in smoke-induced chronic lung inflammation, and with the exception of NF-kappaB pathway, there might be complex mechanism governing molecular dynamics of pro-inflammatory cytokines expression and structural changes in small airways and pulmonary parenchyma in vivo.
Li
Yu-Tao
YT
Department of Respiratory Medicine, Peking University Third Hospital, Beijing, PR China. cloris.lee@hotmail.com
He
Bei
B
Wang
Yu-Zhu
YZ
Wang
Jing
J
D000818:Animals; D008168:Lung; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D011014:Pneumonia / Q000209:etiology* / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity*; D014132:Trachea; D014162:Transfection / Q000379:methods
D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D012906:Smoke
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