Modulation of the chemotactic properties of complement fragments C5a and C3 by the anti-inflammatory agent,SC-41930 |
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Authors: | D J Fretland D L Widomski C P Anglin S Levin T S Gaginella |
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Institution: | 1. Gastrointestinal Diseases Research, Searle Research and Development, 4901 Searle Parkway Skokie, 60077, Skokie, II, USA 2. Department of Pathology, Searle Research and Development, 4901 Searle Parkway Skokie, 60077, Skokie, II, USA
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Abstract: | 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 anin 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 μg C5a significantly (p<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. |
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