Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation

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Abstract

Acute lung injury, a critical illness characterized by acute respiratory failure with bilateral pulmonary infiltrates, remains unresponsive to current treatments. The condition involves injury to the alveolar capillary barrier, neutrophil accumulation and the induction of proinflammatory cytokines followed by lung fibrosis. In the present study, a rabbit model of bleomycin-induced acute lung injury was established to examine the effects of asialoerythropoietin (AEP), an agent with tissue-protective activities, on pulmonary inflammation. Six Japanese white rabbits were randomly divided into two equal groups. Acute lung injury was induced in all rabbits by intratracheally injecting bleomycin. The control group was injected with bleomycin only; the experimental (AEP) group was injected intravenously with AEP (80 μg/kg) prior to the bleomycin injection. Computed tomography (CT) studies were performed seven days later. The CT inflammatory scores of areas exhibiting abnormal density and the pathological inflammatory scores were recorded as a ratio on a 7×7 mm grid. The CT and pathological inflammatory scores were significantly different between the control and AEP groups [122±10 and 16.3±1.5 (controls) vs. 71±8.5 and 9.7±1.4 (AEP), respectively; P<0.01]. Thus, the present study revealed that AEP prevents bleomycin-induced acute lung injury in rabbits.

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Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study.

Jacques Romand, Jesus Villar, Guido Bertolini … (2003)

To re-examine the epidemiology of acute lung injury (ALI) in European intensive care units (ICUs). A 2-month inception cohort study in 78 ICUs of 10 European countries. All patients admitted for more than 4 h were screened for ALI and followed up to 2 months. Acute lung injury occurred in 463 (7.1%) of 6,522 admissions and 16.1% of all mechanically ventilated patients; 65.4% cases occurred on ICU admission. Among 136 patients initially presenting with "mild ALI" (200< PaO2/FiO2 < or =300), 74 (55%) evolved to acute respiratory distress syndrome (ARDS) within 3 days. Sixty-two patients (13.4%) remained with mild ALI and 401 had ARDS. The crude ICU and hospital mortalities were 22.6% and 32.7% (p<0.001), and 49.4% and 57.9% (p=0.0005), respectively, for mild ALI and ARDS. ARDS patients initially received a mean tidal volume of 8.3+/-1.9 ml/kg and a mean PEEP of 7.7+/-3.6 cmH2O; air leaks occurred in 15.9%. After multivariate analysis, mortality was associated with age (odds ratio (OR) =1.2 per 10 years; 95% confidence interval (CI): 1.05-1.36), immuno-incompetence (OR: 2.88; Cl: 1.57-5.28), the severity scores SAPS II (OR: 1.16 per 10% expected mortality; Cl: 1.02-1.31) and logistic organ dysfunction (OR: 1.25 per point; Cl: 1.13-1.37), a pH less than 7.30 (OR: 1.88; Cl: 1.11-3.18) and early air leak (OR: 3.16; Cl: 1.59-6.28). Acute lung injury was frequent in our sample of European ICUs (7.1%); one third of patients presented with mild ALI, but more than half rapidly evolved to ARDS. While the mortality of ARDS remains high, that of mild ALI is twice as low, confirming the grading of severity between the two forms of the syndrome.

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Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.

Nagahisa Yoshimura, M Nagao, Mihori Kita … (2005)

Although vascular endothelial growth factor (VEGF) is a primary mediator of retinal angiogenesis, VEGF inhibition alone is insufficient to prevent retinal neovascularization. Hence, it is postulated that there are other potent ischemia-induced angiogenic factors. Erythropoietin possesses angiogenic activity, but its potential role in ocular angiogenesis is not established. We measured both erythropoietin and VEGF levels in the vitreous fluid of 144 patients with the use of radioimmunoassay and enzyme-linked immunosorbent assay. Vitreous proliferative potential was measured according to the growth of retinal endothelial cells in vitro and with soluble erythropoietin receptor. In addition, a murine model of ischemia-induced retinal neovascularization was used to evaluate erythropoietin expression and regulation in vivo. The median vitreous erythropoietin level in 73 patients with proliferative diabetic retinopathy was significantly higher than that in 71 patients without diabetes (464.0 vs. 36.5 mIU per milliliter, P<0.001). The median VEGF level in patients with retinopathy was also significantly higher than that in patients without diabetes (345.0 vs. 3.9 pg per milliliter, P<0.001). Multivariate logistic-regression analyses indicated that erythropoietin and VEGF were independently associated with proliferative diabetic retinopathy and that erythropoietin was more strongly associated with the presence of proliferative diabetic retinopathy than was VEGF. Erythropoietin and VEGF gene-expression levels are up-regulated in the murine ischemic retina, and the blockade of erythropoietin inhibits retinal neovascularization in vivo and endothelial-cell proliferation in the vitreous of patients with diabetic retinopathy in vitro. Our data suggest that erythropoietin is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy. Copyright 2005 Massachusetts Medical Society.

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Asialoerythropoietin prevents contrast-induced nephropathy.

NORIHISA NITTA, Toshiro Sugimoto, Masakazu Haneda … (2008)

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date (Print): November 2014

Publication date (Electronic): 12 September 2014

Publication date PMC-release: 12 September 2014

Volume: 8

Issue: 5

Pages: 1443-1446

Affiliations

[1 ]Department of Radiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan

[2 ]Department of Pathology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan

Author notes

Correspondence to: Dr Akinaga Sonoda, Department of Radiology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan, E-mail: akinaga@ 123456belle.shiga-med.ac.jp

Article

Publisher ID: etm-08-05-1443

DOI: 10.3892/etm.2014.1960

PMC ID: 4186348

PubMed ID: 25289037

SO-VID: ce5109c3-4dc6-4c8c-9ba6-060fa509cc21

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This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

History

Date received : 19 February 2014

Date accepted : 11 August 2014

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Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation

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Inflamed lung in vitro co-culture models

Most cited references 16

Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study.

Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.

Asialoerythropoietin prevents contrast-induced nephropathy.

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