Abstract
BackgroundTracheal injury is a common clinical condition that still lacks an effective therapy at present. Stimulation of epithelial sodium channel (ENaC) increases Na+ transport, which is a driving force to keep tracheal mucosa free edema fluid during tracheal injury. Ferulic acid (FA) has been proved to be effective in many respiratory diseases through exerting anti-oxidant, anti-inflammatory, and anti-thrombotic effects. However, these studies rarely involve the level of ion transport, especially ENaC.MethodsC57BL/J male mice were treated intraperitoneally with normal saline or FA (100 mg/kg) 12 h before, and 12 h after intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg), respectively. The effects of FA on tracheal injury were not only assessed through HE staining, immunofluorescence assay, and protein/mRNA expressions of ENaC located on tracheas, but also evaluated by the function of ENaC in mouse tracheal epithelial cells (MTECs). Besides, to explore the detailed mechanism about FA involved in LPS-induced tracheal injury, the content of cyclic guanosine monophosphate (cGMP) was measured, and Rp-cGMP (cGMP inhibitor) or cGMP-dependent protein kinase II (PKGII)-siRNA (siPKGII) were applied in primary MTECs, respectively.ResultsHistological examination results demonstrated that tracheal injury was obviously attenuated by pretreatment of FA. Meanwhile, FA could reverse LPS-induced reduction of both protein/mRNA expressions and ENaC activity. ELISA assay verified cGMP content was increased by FA, and administration of Rp-cGMP or transfection of siPKGII could reverse the FA up-regulated ENaC protein expression in MTECs.ConclusionsFerulic acid can attenuate LPS-induced tracheal injury through up-regulation of ENaC at least partially via the cGMP/PKGII pathway, which may provide a promising new direction for preventive and therapeutic strategy in tracheal injury.
Highlights
Normal tracheal lumen is lined with polarized columnar cells with cilia on the top, constituting the predominant structural barrier to pathogens and a variety of environmental agents [1], which represents a pivotal site for the innate immunity and host defense [2]
Ferulic acid (FA) attenuated LPS‐induced tracheal injury The intratracheal surface is lined with pseudostratified ciliated columnar epithelium, and we applied hematoxylin and eosin (HE) staining to evaluate the pathological morphology of tracheal injury in mice
Our results showed that LPS significantly decreased both the height of tracheal epithelium and number of epithelial cells per area (Fig. 1B, C, P < 0.001, compared with Control group), which was reversed by the co-administration of FA (P < 0.001, compared with LPS group)
Summary
Normal tracheal lumen is lined with polarized columnar cells with cilia on the top, constituting the predominant structural barrier to pathogens and a variety of environmental agents [1], which represents a pivotal site for the innate immunity and host defense [2]. It has been reported that abnormalities in tracheal cilia structure and function lead to a decrease of ENaC activity, which contributes to the occurrence and development of chronic respiratory diseases [11]. Stimulation of epithelial sodium channel (ENaC) increases Na+ transport, which is a driving force to keep tracheal mucosa free edema fluid during tracheal injury. Ferulic acid (FA) has been proved to be effective in many respiratory diseases through exerting anti-oxidant, anti-inflammatory, and anti-thrombotic effects. These studies rarely involve the level of ion transport, especially ENaC
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