Modulation of the chemotactic properties of complement fragments C5a and C3 by the anti-inflammatory agent, SC-41930.
Cleavage of the fifth component of complement yields C5a, a potent neutrophil (PMN) and eosinophil chemoattractant, and modulator of microvascular permeability. Similarly, but to a lesser degree, C3 increases vascular permeability and histamine release. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl- 2H-1-benzopyran-2-carboxylic acid), an orally-active antiinflammatory agent was tested in an in vivo model of dermal PMN chemotaxis induced by r-hu-C5a and hu-C3. Intradermal injection of C5a in the guinea pig resulted in a significant dose-dependent influx of PMNs at 4 hours as assessed by the dermal levels of myeloperoxidase (MPO). SC-41930 (20 mg/kg) given orally to guinea pigs with intradermal injections of 1 microgram C5a significantly (p less than 0.001) reduced dermal MPO content. SC-41930 was less potent against C3, requiring 40 mg/kg to significantly reduce dermal MPO levels. Agents such as SC-41930, which nullify complement's proinflammatory properties, may well have therapeutic potential.
Fretland
D J
DJ
Department of Pathology, Searle Research and Development, Skokie, Il 60077.
Widomski
D L
DL
Anglin
C P
CP
Levin
S
S
Gaginella
T S
TS
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003176:Complement C3 / Q000494:pharmacology*; D015936:Complement C5a / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000201:enzymology
D001578:Benzopyrans; D003176:Complement C3; D011994:Recombinant Proteins; C059950:SC 41930; D015936:Complement C5a; D009195:Peroxidase