Head Injury and Neuroanesthesia

Erythropoietin Administration Modulates Pulmonary Nrf2 Signaling Pathway After Traumatic Brain Injury in Mice

Jin W, Wu J, Wang H, et al (Med School of Nanjing Univ, China) J Trauma 71:680-686, 2011^§

Abstract

Background

In our previous studies, antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway has been shown to play an important role in protecting traumatic brain injury (TBI)-induced acute lung injury (ALI). This study was designed to explore whether recombinant human erythropoietin (rhEPO) administration modulates pulmonary Nrf2 signaling pathway in a murine TBI model.

Methods

Closed head injury was made by Hall’s weight-dropping method. The rhEPO was administered at a dose of 5,000 IU/kg 30 minutes after TBI. Pulmonary capillary permeability, wet or dry weight ratio, apoptosis, Nrf2 and its downstream cytoprotective enzymes including NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase were investigated at 24 hours after TBI.

Results

We found that treatment with rhEPO markedly ameliorated TBI-induced ALI, as characterized by decreased pulmonary capillary permeability, wet or dry weight ratio, and alveolar cells apoptosis. Administration of rhEPO also significantly upregulated the mRNA expressions and activities of Nrf2 signaling pathway-related agents, including Nrf2, NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase.

Conclusions

The results of this study suggest that post-TBI rhEPO administration may induce Nrf2-mediated cytoprotective response in the lung, and this may be a mechanism whereby rhEPO reduces TBI-induced ALI (Figs 3 and 5).

Figure 3 TUNEL immunohistochemistry staining of lung in sham group, TBI group, and TBI + rhEPO group (n = 6). (A) Sham group mice showing few TUNEL positive cells (stained brown); (B) TBI group mice showing more TUNEL positive cells; (C) TBI + rhEPO group mice showing less TUNEL positive cells than TBI group; and (D) the rhEPO treatment significantly decreased the AI in the lung tissue after TBI. **p < 0.01 versus sham group and #p < 0.05 versus TBI group. Scale bars, 50 μm. For interpretation of the references to color in this figure legend, the reader is referred to web version of this article. (Reprinted from Jin W, Wu J, Wang H, et al. Erythropoietin administration modulates pulmonary Nrf2 signaling pathway after traumatic brain injury in mice. J Trauma. 2011;71:680-686, with permission from Lippincott Williams & Wilkins.)

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