Silencing airway epithelial cell-derived hepcidin exacerbates acute lung injury by regulating the intracellular iron status in alveolar macrophages (INM7P.434)

Abstract

Abstract Objective: Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infectious and inflammatory disease such as acute lung injury. Methods: Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice twice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the 7-day survival rate were assessed. The local and systemic iron content was assayed. Results: The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased the mortality. Moreover, the knockdown of hepcidin in airway epithelial cells led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages, but did not affect the STAT3/SOCS3 axis. Conclusions: Airway epithelial cell-derived hepcidin plays an important role in protection against acute lung injury via regulating the intracellular iron status in alveolar macrophages.