title: Activation of hypoxia-inducible factor-1alpha via nuclear factor-kappa B in rats with chronic obstructive pulmonary disease.
abstract: Accumulating data suggested that hypoxia inducible factor (HIF)-1alpha plays an important role in the evolution and propagation of the inflammatory process. To characterize the activation of HIF-1alpha in rats with chronic obstructive pulmonary disease (COPD) and examine the possible role of nuclear factor (NF)-kappaB in this process, rats were challenged by introtracheal instillation of lipopolysaccharide (LPS) and exposure to cigarette smoke. Pyrrolidine dithiocarbamate (PDTC) was administered via the oral route 1 h before LPS or cigarettes administration. Four weeks later, pulmonary function and histology were tested; bronchoalveolar lavage fluid (BALF) and arterial blood gases were assayed. Activation of pulmonary NF-kappaB was assessed by quantitative PCR, immunoblot analysis, and electrophoretic mobility shift assay, respectively. Results showed that LPS and smog induced the characteristics of COPD seen in human. PDTC alleviated the development of COPD and the levels of cytokines in BALF of PDTC+COPD group were significantly decreased compared with that of COPD group. The activation of pulmonary NF-kappaB was inhibited by PDTC and the accumulation of HIF-1alpha gene expression in the COPD group was attenuated by PDTC pretreatment. Furthermore, the mRNA levels of HIF-1alpha target genes heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were parallel to the attenuation of HIF-1alpha by PDTC. These findings indicated that the activation of HIF-1alpha pathway via NF-kappaB contributes to the development of COPD, and administration of NF-kappaB inhibitor may attenuate the development of COPD.
authors: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China.
authors: Hong
authors: H
authors: Jiang
authors: Yesen
authors: Y
authors: Zhu
authors: Hui
authors: H
authors: Xu
authors: Yu
authors: Y
authors: Sun
authors: Qifang
authors: Q
authors: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects; D013859:Thiocarbamates / Q000008:administration & dosage / Q000494:pharmacology; D014026:Nicotiana / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011759:Pyrrolidines; D012906:Smoke; D013859:Thiocarbamates; D042461:Vascular Endothelial Growth Factor A; C020972:pyrrolidine dithiocarbamic acid; D051547:Heme Oxygenase-1