Retinoic acid syndrome in NOD/scid mice induced by injecting an acute promyelocytic leukemia cell line.
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 x 10(7)) 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.
Ninomiya
M
M
Department of Hematology, Nagoya University Hospital, Nagoya, Japan.
Kiyoi
H
H
Ito
M
M
Hirose
Y
Y
Ito
M
M
Naoe
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007275:Injections, Intravenous; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011654:Pulmonary Edema / Q000209:etiology; D012074:Remission Induction; D013577:Syndrome; D014212:Tretinoin / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D019743:Chemokines, CXC; D014212:Tretinoin; D004317:Doxorubicin