Comparative analysis of pathologic processes developing in mice housed in SPF vs non-SPF conditions and treated with cyclophosphamide and dsDNA preparation

In our earlier studies, we observed that when mice are treated with cyclophosphamide and fragmented exogenous dsDNA (18–30h post cytostatic treatment), they develop a very characteristic set of symptoms and 80–90% of such animals succumb within 6–25 days. This was called “delayed death” phenomenon,...

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Published in:Pathology, research and practice research and practice, 2015-10, Vol.211 (10), p.754-758
Main Authors: Dolgova, Evgeniya V., Efremov, Yaroslav R., Taranov, Oleg S., Potter, Ekaterina A., Nikolin, Valeriy P., Popova, Nelly A., Omigov, Vladimir V., Chernykh, Elena R., Proskurina, Anastasia S., Bogachev, Sergey S.
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - cytology
B-Lymphocytes - drug effects
Bone Marrow Cells - cytology
Bone Marrow Cells - drug effects
Cell Differentiation - drug effects
Cell Lineage - drug effects
Cells, Cultured
Cyclophosphamide - pharmacology
DNA - metabolism
Double-stranded DNA
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - drug effects
Lymphoid progenitors
Mice
Mice, Inbred CBA
Opportunistic infection
SPF mice
Systemic inflammation
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Summary:In our earlier studies, we observed that when mice are treated with cyclophosphamide and fragmented exogenous dsDNA (18–30h post cytostatic treatment), they develop a very characteristic set of symptoms and 80–90% of such animals succumb within 6–25 days. This was called “delayed death” phenomenon, and the gap between cyclophosphamide and DNA injections required for such phenotype to develop was termed “death window”. We established that mice succumbed to multi-organ failure, which was caused by systemic inflammation and sepsis. These processes unfolded along with accidental involution of lymphoid organs, which resulted from the failure of CD34+ hematopoietic stem cells to differentiate into lymphoid lineage progenitors. Here we compare SPF and non-SPF animals, and demonstrate that the major cause of systemic inflammation and sepsis observed upon such treatments is activation of an opportunistic infection. Mice of the same strain (CBA) housed under SPF conditions do not develop the characteristic symptoms, nor do they become moribund. Yet, regardless of the breeding conditions, upon synergistic action of cyclophosphamide and dsDNA, CD34+ hematopoietic stem cells consistently fail to give rise to lymphoid lineage progenitors. We demonstrate that this differentiation defect is reversible and that population of lymphoid progenitors is restored by day 29 after cyclophosphamide injection.
ISSN:0344-0338
1618-0631
DOI:10.1016/j.prp.2015.07.002