Formaldehyde exacerbates asthma in mice through the potentiation of HIF-1-mediated pro-inflammatory responses in pulmonary macrophages

Exposure to formaldehyde (FA) has been indicated to be positively correlated with increased incidence of allergic asthma in many epidemiological and experimental studies. However, few studies have ever addressed the molecular basis of the correlation. In the present study, it was found that inhaling 2.0 mg/m(3) FA for 2 weeks could exacerbate the pulmonary inflammation and mucus over-accumulation in OVA-induced murine asthmatic model. The pro-inflammatory cytokines, such as IL-1 beta, TNF-alpha, IL-6 and IL-8, were increased in lung and serum of FA-exposed asthmatic mice. The contribution of HIF-1 alpha signaling in FA-exacerbated allergic asthma was confirmed by bioinformatic analysis. HIF-1 alpha and its downstream proteins, which are known as mediators of glycolysis, were found to be upregulated by 50 mu M FA, and the FA-enhanced of glycolysis was reversed by inhibition of HIF-1 alpha with PX-478 in vitro and YC-1 in vivo. Furthermore, it was confirmed that inhibition of HIF-1 alpha signaling could restrain the macrophagic inflammatory responses and asthma exacerbation induced by FA. Collectively, these results revealed that FA could exacerbate asthma through the potentiation of HIF-1 alpha-mediated inflammatory responses in macrophages, which also indicated the universal roles of FA-triggered macrophage metabolic and functional alterations in inflammatory or allergic diseases.