AJ Gray, JE Bishop, JT Reeves, RP Mecham and GJ Laurent
Developmental Lung Biology Laboratory, University of Colorado, Denver, USA.

The conversion by thrombin of soluble plasma fibrinogen to an insoluble fibrin matrix is central to hemostasis and subsequent wound healing. Fibroblasts adhere to and rapidly grow into fibrin clots, resulting in collagen deposition and, ultimately, scar formation. Although a number of soluble mediators have been implicated in this process, a role for fibrin(ogen) itself has not been described. The present study further investigated the nature of mitogenic activity remaining in solution after in vitro fibrin clot formation. Liquid expressed from a fibrin clot (clot supernatant) elicited a mitogenic response of up to 83 +/- 4.7% above media control. Upon addition of a polyclonal fibrinogen antibody, this activity was reduced by 50%. The remaining activity was attributed to the presence of thrombin and was neutralized by the addition of a specific thrombin inhibitor. Fibrinogen cleavage products were separated by molecular sieve chromatography and the mitogenic potential of each fraction assessed. A peak of activity was observed in fractions containing proteins with apparent molecular weights of 200 to 300 kD. Enhanced chemiluminescence Western blotting of these fractions established the presence of several fibrin(ogen)-derived protein bands. It is therefore proposed that thrombin cleavage of fibrinogen, in addition to producing fibrin, generates high-molecular-weight soluble cleavage products that may play an important role during normal wound healing and in the pathogenesis of disease states associated with vascular leakage and fibrosis.

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