Abstract

Acute chest syndrome (ACS), the most common cause of death among adults with sickle cell disease and a significant threat to children, is often triggered by bone marrow embolization, especially among adults. We have recently developed a sickle transgenic mouse model for acute chest that consists of injecting a mixture of bone marrow and mouse fat into the tail vein of a sickle transgenic partial knockout mouse. The mouse used was a NY1 partial KO expressing 100% human α and 55% βS globins. Mice were injected with bone marrow (BM) from two femurs (about 15 mg) and purified peritoneal fat (about 15 mg, as murine BM lacks fat), and examined at 0, 6, 24, and 48 hours post-injection. Creatine kinase (CK), predominantly the MM form, increased above baseline levels at 6, 24, and 48 hours in NY1 partial KO mice; whereas, in control C57Bl mice, there was an initial increase at 6 hours with a return to baseline values at 24 and 48 hours. sVCAM levels were not significantly different between C57Bl and NY1 partial KO mice at baseline: 717±203 in C57Bl mice and 752±147 in NY1 partial KO mice (N=15 and 11, respectively); after injection of fat/BM sVCAM levels nearly doubled in NY1 partial KO mice and remained elevated at 48 hours. In fat/BM injected C57Bl mice, sVCAM levels remained essentially constant from 0 to 48 hours. Mouse lungs were harvested at 48 hours after saline perfusion and inflated with 10% phosphate buffered formalin. The hematoxylin and eosin stained lung sections were normal among the C57Bl control mice examined 48 hours after fat/BM injection, but among NY1 partial KO mice edema, inflammation, and congestion were found with numerous red cells entrapped, despite saline perfusion. In summary, this preparation shows promise as an animal model of ACS. Pulmonary edema and elevated levels of sVCAM are characteristic features of ACS in sickle cell patients and are found, after fat/BM injection, in our sickle mice but not in control mice. The mice survived the procedure, indicating that it will be possible to study the natural course of lung injury and interventions that may ameliorate injury.

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