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The potentiation of human C1-inhibitor by dextran sulphate is transient in vivo: studies in a rat model
C1-inhibitor (C1-Inh) is an important regulator of inflammatory reactions because it is a potent inhibitor of the contact and complement system. C1-Inh application in inflammatory disease is, however, restricted because of the high doses required. The glycosaminoglycan-like molecule dextran sulphate...
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Published in: | International immunopharmacology 2001-08, Vol.1 (8), p.1583-1595 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | C1-inhibitor (C1-Inh) is an important regulator of inflammatory reactions because it is a potent inhibitor of the contact and complement system. C1-Inh application in inflammatory disease is, however, restricted because of the high doses required.
The glycosaminoglycan-like molecule dextran sulphate (DXS) enhances C1-Inh function in vitro. Hence, we investigated whether co-administration with dextran sulphate reduces the amount of C1-Inh required, through enhancement in vivo. C1-Inh potentiation was measured in a newly developed C1s-inactivation assay that is based on activation of C4 by purified C1s. Activated C4 in rat plasma was quantified with a newly developed ELISA. Human C1-Inh (2.5 μM) inhibited C1s in rat plasma 55-fold faster in the presence of dextran sulphate (15 kDa, 5 μM). To study the stability of the complex in vivo, rats were given a mixture of C1-Inh (10 mg/kg) and dextran sulphate (3 mg/kg). C1-Inh activity during 5 h was analyzed ex vivo with the C1s inactivation assay. The noncovalent C1-Inh–dextran sulphate complex resulted in a transient enhancement of the inhibitory capacity of C1-Inh, lasting for 60–90 min. Dextran sulphate did not affect plasma clearance of C1-Inh.
We conclude that the enhanced inhibitory capacity of C1-Inh complexed to dextran sulphate is transient in vivo. Hence, co-administration of these compounds seems a feasible approach to achieve short-term inhibition of complement in vivo. |
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ISSN: | 1567-5769 1878-1705 |
DOI: | 10.1016/S1567-5769(01)00073-X |