Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation.
OBJECTIVE
Clinically, the vascular pathobiology of human sickle cell disease includes an abnormal state of chronic inflammation and activation of the coagulation system. Since these biologies likely underlie development of vascular disease in sickle subjects, they offer attractive targets for novel therapeutics. Similar findings characterize the sickle transgenic mouse, which therefore provides a clinically relevant inflammation model.


METHODS
The authors tested two polyhydroxyphenyl hydroxamic acid derivatives, didox and trimidox, in sickle transgenic mice. Animals were examined by intravital microscopy (cremaster muscle and dorsal skin fold preparations) and by histochemistry before and after transient exposure to hypoxia, with versus without preadministration of study drug. Previous studies have validated the application of hypoxia/reoxygenation to sickle transgenic mice as a disease-relevant model.


RESULTS
Animals pretreated with these agents exhibited marked improvements in leukocyte/ endothelial interaction, hemodynamics and vascular stasis, and endothelial tissue factor expression. Thus, these drugs unexpectedly exert powerful inhibition on both the inflammation and coagulation systems.


CONCLUSIONS
Each of these changes is expected to be therapeutically beneficial in systemic inflammatory disease in general, and in sickle disease in particular. Thus, these novel compounds offer the advantage of having multiple therapeutic benefits in a single agent.
Kaul
Dhananjay K
DK
Department of Medicine, Albert Einstein College of Medicine, New York, Bronx, USA.
Kollander
Rahn
R
Mahaseth
Hemchandra
H
Liu
Xiao-Du
XD
Solovey
Anna
A
Belcher
John
J
Kelm
Robert J
RJ
Vercellotti
Gregory M
GM
Hebbel
Robert P
RP
D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001550:Benzamidines / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D002450:Cell Communication / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013925:Thromboplastin / Q000096:biosynthesis
C074761:3,4,5-trihydroxybenzamidoxime; D001550:Benzamidines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013925:Thromboplastin; C035419:3,4-dihydroxybenzohydroxamic acid