Activation of hypoxia-inducible factor-1α via nuclear factor-κB in rats with chronic obstructive pulmonary disease

Accumulating data suggested that hypoxia inducible factor (HIF)-1 alpha plays an important role in the evolution and propagation of the inflammatory process. To characterize the activation of HIF-1 alpha in rats with chronic obstructive pulmonary disease (COPD) and examine the possible role of nuclear factor (NF)-kappa B 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-kappa B 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-kappa B was inhibited by PDTC and the accumulation of HIF-1 alpha gene expression in the COPD group was attenuated by PDTC pretreatment. Furthermore, the mRNA levels of HIF-1 alpha target genes heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were parallel to the attenuation of HIF-1 alpha by PDTC. These findings indicated that the activation of HIF-1 alpha pathway via NF-kappa B contributes to the development of COPD, and administration of NF-kappa B inhibitor may attenuate the development of COPD.