Therapeutic effects of erythropoietin in murine models of... : Critical Care Medicine (original) (raw)

Clinical Investigations

Aoshiba, Kazutetsu MD; Onizawa, Shigemitsu MD; Tsuji, Takao MD; Nagai, Atsushi MD

From the First Department of Medicine, Tokyo Women’s Medical University, Tokyo, Japan.

This study was supported by a grant to the Respiratory Failure Research Group from the Ministry of Health, Labour and Welfare, Japan.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Abstract

Objective:

Erythropoietin has recently emerged as a cytoprotective cytokine, which possesses the ability to protect many tissues, including the brain, heart, and kidneys, against ischemia or traumatic injury. We investigated the therapeutic effects of erythropoietin in a murine model of endotoxin shock.

Design:

Prospective, randomized study.

Setting:

University-based research laboratory.

Subjects:

Male BALB/c mice.

Interventions:

Mice intraperitoneally received either lipopolysaccharide (LPS) from Escherichia coli or vehicle. Erythropoietin was administered at a dose of 1000 IU/kg subcutaneously at different time points after LPS administration. We also investigated the effect of erythropoietin on the development of septic shock caused by cecal perforation.

Measurements and Main Results:

Treatment of mice with erythropoietin, within 2 hours after LPS administration, improved the mortality rate. Treatment of cecal perforated mice with erythropoietin extended survival by 12 hours, but all animals died by 72 hours in both groups. Erythropoietin attenuated apoptosis in the lungs, liver, small intestine, thymus, and spleen, as assessed by terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling staining, active caspase-3 immunostaining and immunoblotting, and measurements of caspase-3/7 activity. Erythropoietin also reduced inducible nitric oxide synthase expression, nitric oxide production, peroxynitrite formation, and tissue hypoxia. In contrast, erythropoietin did not affect the degree of LPS-induced inflammation, as assessed by measurements of blood levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, growth-related oncogene/keratinocyte-derived cytokine, and high mobility group box 1, the phosphorylation levels of nuclear factor κB, and the number of neutrophils infiltrating the lungs and the liver.

Conclusions:

The results of the study demonstrate that administration of a large dose of erythropoietin after induction of experimental endotoxemia improved survival and that the beneficial effects of erythropoietin were associated with inhibition of apoptosis, nitric oxide production, and tissue hypoxia, without alterations in inflammatory responses.