Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung

Allison Fryer, Yuh Chin Huang, Gopna Rao, David Jacoby, Edward Mancilla, Richard Whorton, Claude A. Piantadosi, Thomas Kennedy, John Hoidal

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Heparin has potential use as an antiinflammatory treatment in many lung diseases but its therapeutic use is limited by inherent anticoagulant activity. The anticoagulant nature of heparin can be eliminated by a number of chemical treatments, but often not without loss of other important pharmacological activities. Lyophilization of porcine mucosal heparin under extreme alkaline conditions (pH ≤ 13) produces a nonanticoagulant heparin remarkable for the selective loss of only 2-O and 3-O sulfates, leaving 6-O and N-sulfates intact. In contrast to the commonly used nonanticoagulant analog N-desulfated, N-reacetylated heparin, selectively O-desulfated heparin retains potent activity as an inhibitor of the cationic neutrephil proteases human leukocyte elastase and cathepsin G, both in vitro and in vivo. Selectively O-desulfated heparin also inhibits complement lysis of erythrocytes, prevents ischemia-reperfusion [injury of the lung, remains a potent antiproliferative treatment for cultured airway smooth muscle and normalizes altered neuronal M2 muscarinic receptor sensitivity and bronchial hyperreactivity after antigen challenge. These retained pharmacologic properties suggest possible use of this new nonanticoagulant heparin for the treatment of a variety of lung disorders.

Original languageEnglish (US)
Pages (from-to)208-219
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume282
Issue number1
StatePublished - Jul 1 1997
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Fryer, A., Huang, Y. C., Rao, G., Jacoby, D., Mancilla, E., Whorton, R., Piantadosi, C. A., Kennedy, T., & Hoidal, J. (1997). Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung. Journal of Pharmacology and Experimental Therapeutics, 282(1), 208-219.