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 (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 microM) inhibited C1s in rat plasma 55-fold faster in the presence of dextran sulphate (15 kDa, 5 microM). 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.
Bos
I G
IG
Department of Immunopathology, CLB and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, The Netherlands. I_Bos@clb.nl
van Mierlo
G J
GJ
Bleeker
W K
WK
Rigter
G M
GM
te Velthuis
H
H
Dickneite
G
G
Hack
C E
CE
D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000494:pharmacology*; D003167:Complement Activation; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism / Q000494:pharmacology*; D050718:Complement C1 Inhibitor Protein; D003173:Complement C1s / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D016264:Dextran Sulfate / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051381:Rats; D017208:Rats, Wistar
D000925:Anticoagulants; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D003181:Complement C4; D016264:Dextran Sulfate; D003173:Complement C1s