Iron Regulatory Protein 2 Deficiency Is Protective Against Resistive Breathing-induced Pulmonary Inflammation.

Abstract

IRP2 (iron regulatory protein 2), a post-transcriptional regulator of cellular iron metabolism, has been associated with susceptibility to chronic obstructive pulmonary disease. Resistive breathing (RB) is the hallmark of the pathophysiology of obstructive airway diseases, especially during exacerbations, when increased mechanical stress is imposed on the lung. We have previously shown that RB, through tracheal banding, mimicking severe airway obstruction, induces pulmonary inflammation and injury in previously healthy mice. To characterize the role of IRP2 in RB-induced lung injury, wild-type and Irp2^-/- mice were subjected to tracheal banding surgery. RB increased tissue elasticity and viscance in wild-type but not in Irp2^-/- mice, denoting that the latter were protected against lung injury. Moreover, Irp2^-/- mice exhibited a lower score of lung inflammation. In addition, only wild-type but not Irp2^-/- mice responded to RB by increasing BAL cellularity due to higher macrophage count, which was accompanied by elevated BAL IL-1β and IL-6 concentrations. Lung proteomics and functional enrichment analysis revealed significant differences among wild-type and Irp2^-/- mice in RB-induced regulation of proteins involved in inflammatory and defense response pathways but also of many proteins with unknown function. We conclude that IRP2 supports proinflammatory activities in the lungs, whereas its deficiency protects against RB-induced pulmonary inflammation via remodeling of the lung proteome.