Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation

Dhananjay K. Kaul, Rahn Kollander, Hemchandra Mahaseth, Xiao Du Liu, Anna Solovey, John D Belcher, Robert J. Kelm, Gregory M Vercellotti, Robert P Hebbel

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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. Method: 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.

Original languageEnglish (US)
Pages (from-to)489-497
Number of pages9
JournalMicrocirculation
Volume13
Issue number6
DOIs
StatePublished - Sep 2006

Keywords

  • Anti-inflammatory
  • Endothelium
  • Hydroxyurea
  • Leukocyte
  • Sickle
  • Tissue factor

Fingerprint Dive into the research topics of 'Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation'. Together they form a unique fingerprint.

Cite this