Effect of D-penicillamine pre- and post-implantation treatment on formation of sponge-induced granulation tissue in rats.

DNA, collagen and sulfated glycosaminoglycans (GAGs) of rat sponge granulation tissue were studied after 42 days of D-penicillamine (D-pen) treatment at 100, 250 or 500 mg/kg/day, starting 10 days before or 28 days after induction of granulation tissue formation. The effects were compared with those observed when the same dosage was started at the onset of the granulation tissue formation and with pair-fed controls. D-pen stimulated the cell invasion into the sponge implants, as manifested by an increased DNA content, particularly with pre-treatment. Pre-treatment reduced the net deposition of of collagen per cell as assessed by the lower hydroxyproline/DNA ratio, at the lower dose leading to reduced collagen concentration. The total amount of granulation tissue collagen remained essentially unaffected within the observation period. Salt-soluble collagen was augmented in a dose-dependent manner, irrespective of treatment protocol, signifying decreased collagen cross-linking. Both pre- and post-implantation treatment enhanced the radiosulfate incorporation into sulfated GAGs, regardless of dose, whereas treatment from the day of sponge implantation had no effect. It is concluded that D-pen enhances the early connective tissue response to injury. Reduction of collagen cross-linking and net collagen deposition, concomitant with stimulation of the proteoglycan metabolism, may pertain to the antirheumatoid activity of D-pen. The observations suggest that long-term administration of D-pen, starting before new attacks of arthritis, may be most effective in controlling developing articular fibrosis.