Anti-inflammatory and regenerative effects of hypoxic signaling inhibition in a model of COpD
The aim of this study was to investigate anti-inflammatory and regenerative effects of inhibited activation of hypoxic signaling in COPD model using cyclooxygenase-2 (COX-2)-dependent pro-inflammatory cascade inhibition. Methods. COPD was modelled in rats by nitrogen dioxide (NO2, 30-40 mgxm<sup>-3</sup>) exposure for 90 days. Celecoxib was used as COX-2 inhibitor. The study group rats were given celecoxib (25 mgxm<sup>-3</sup>) through an esophageal probe after 30 days of exposure. Control rats were given saline solution. The group 3 rats were intact. The rats were put out of the experience using cervical dislocation after 60 and 90 days of NO2 exposure. Bronchoalveolar lavage fluid (BALF) cytology was analyzed. COX-2, hypoxia-inducible factor-1a (HIF-1a), interleukin-17 (IL-17), and surfactant protein D (SP-D) were measured in BALF using ELISA method. Histological examination of the lung tissue was also performed. Results. 90-day exposure of NO2 resulted in 7.7-fold increase in BALF neutrophil count compared to that in intact rats. Pro-inflammatory mediators (COX-2, HIF-1a, and IL-17) significantly increased and SP-D level decreased in BALF. Administration of celecoxib was accompanied by normalization of BALF cytology profile and decrease in COX-2, HIF-1a, and IL-17 levels in BALF; this could indicate a reduction in the hypoxic signaling activity and in inflammation. The growth of SP-D concentration could be considered as a result of the alveolar epithelium restoration. This was confirmed by histological examination of the lung tissue. Conclusion. COX-2 inhibition suppressed HIF-1a-signaling and decreased the lung inflammation. The results confirm a functional and regulatory relationship between HIF-1a and COX-2 signaling cascades that could be a therapeutic target for preventing the progression of inflammation and airway remodeling in COPD.