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Retinoic acid syndrome in NOD/scid mice induced by injecting an acute promyelocytic leukemia cell line

Leukemia volume 18, pages 442–448 (2004)Cite this article

Abstract

All-trans retinoic acid (ATRA) induces complete remission in patients with acute promyelocytic leukemia (APL). However, ATRA sometimes causes retinoic acid syndrome (RAS) characterized by respiratory distress, pleural effusions, fever and weight gain. To investigate the pathophysiology of RAS, we generated an animal model by injecting an APL cell line, NB4, into immunodeficient mice. When NOD/scid mice were injected intravenously with fully differentiated NB4 cells (1 × 107) and then given a daily administration of ATRA, three of 12 mice died of pulmonary edema within 14 days. Pathologically, dilated lung capillary vessels and alveolar effusions were observed. After the injection, NB4 cells were detected in the lung within 2 days and in the pleural effusion later on. The gene expression levels of CXC chemokines (MIP-2 and KC) and ICAM-1 were increased in the lung and heart by the ATRA administration. In immunohistochemical analyses, MIP-2 was clearly detected in alveolar macrophages of the lung in mice with RAS. Dexamethasone treatment prevented the development of RAS and decreased the CXC chemokine mRNA expression in the lung. These findings suggested that the activation of adhesion molecules for leukocytes and expression of CXC chemokines in the lung are closely involved in triggering RAS.

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Acknowledgements

This study was performed in cooperation with Research on the Human Genome, Tissue Engineering, and Food Biotechnology from the Ministry of Health and Welfare. We thank Ms Manami Kira, Ms Kyoko Aoyama and Mr Takashi Iwasaki for secretarial and technical assistance. This work was supported by Grants-in-Aid from the Ministry of Health and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations

  1. Department of Hematology, Nagoya University Hospital, Nagoya, Japan

    M Ninomiya & T Naoe

  2. Department of Infectious Diseases, Nagoya University Hospital, Nagoya, Japan

    H Kiyoi & Y Hirose

  3. Department of Pathology, Nagoya University Hospital, Nagoya, Japan

    M Ito

  4. Central Institute for Experimental Animals, Kawasaki, Japan

    M Ito

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  1. M Ninomiya
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Correspondence to T Naoe.

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Ninomiya, M., Kiyoi, H., Ito, M. et al. Retinoic acid syndrome in NOD/scid mice induced by injecting an acute promyelocytic leukemia cell line. Leukemia 18, 442–448 (2004). https://doi.org/10.1038/sj.leu.2403284

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