SELECTIVE O-DESULFATION PRODUCES NONANTICOAGULANT HEPARIN THAT RETAINS PHARMACOLOGICAL ACTIVITY IN THE LUNG

Heparin has potential use as an antiinflammatory treatment in many lun g diseases but its therapeutic use is limited by inherent anticoagulan t activity. The anticoagulant nature of heparin can be eliminated by a number of chemical treatments, but often not without loss of other im portant pharmacological activities. Lyophilization of porcine mucosal heparin under extreme alkaline conditions (pH greater than or equal to 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 pote nt activity as an inhibitor of the cationic neutrophil proteases human leukocyte elastase and cathepsin G, both in vitro and in vivo. Select ively O-desulfated heparin also inhibits complement lysis of erythrocy tes, prevents ischemia-reperfusion injury of the lung, remains a poten t antiproliferative treatment for cultured airway smooth muscle and no rmalizes altered neuronal M-2 muscarinic receptor sensitivity and bron chial hyperreactivity after antigen challenge. These retained pharmaco logic properties suggest possible use of this new nonanticoagulant hep arin for the treatment of a variety of lung disorders.