The alterations in fibrinogen and fibronectin contributing to their deposition as subendothelial fibrinoid in vascular lesions are frequently only remotely refelected in abnormalities discernible systemically from peripheral blood, the principal source of working material usually employed for study of the etiology of coagulative aspects of disease. Zonal immobilization procedures employing glyoxyl agarose for immunoelectrophoretic characterization of highly insoluble proteins and their derivatives not amenable to analysis by previous methodologies provide new means of characterizing modifications of these proteins as they occur in vascular tissue. Further, a novel, direct blot method for rapid screening of hybridoma cultures for monoclonal antibody secretion has been devised for efficient production of new reagents for characterizing specific alterations of the proteins definable with synthetic peptides. Application of these technologies will be directed to characterizing the course of fibrin(ogen) deposition in 1) the necrotizing vascular lesions of experimentally induced malignant hypertension in rats, and 2) arteriosclerotic lesions from human necropsies. The experimental studies with rats involve aortic ligation between the renal arteries and induce a 30% incidence of fibrinoid rich lesions with associated medial atrophy characteristic of malignant hypertension and resembling lesions also seen in scleroderma, polyarteritis nodosa, stroke, and other necrotizing vascular diseases in man, while the non-malignant course yields hypertrophic alterations of the vasculature identical to those seen in benign hypertension. The divergent course of the vascular alterations in malignant vs. benign hypertension, and the ability to diagnose predisposition towards these courses near the outset in this model provide opportunity to chart not only the cause and effects of fibrinogen/fibrinoid transition, but also to assess effects of early intervention for test of hypothesized predisposing factors. A high degree of cross-linking of fibrinogen and fibronectin uncovered thus far as one of the most reliable indications of the malignant course, and identification of hormonal and humoral alterations appearing to perpetuate the depositional process offer prospect of defining the factors underlying the disparate vascular changes. Similarly, fibrinoid deposition may contribute variably depending on underlying factors in diseases of man, and the superimposed effects may determine the course of vascular alterations. Proposed studies on arteriosclerotic lessions available from surgical and autopsy specimens will be directed to test indications of cross-linking as a determinant for accumulation and persistence of fibrinoid in the lesions, and to compare apparent effects of fibrinoid in this disease and those contributing to the necrotizing lesions of malignant hypertension.
| Dardik, B N; Shainoff, J R (1985) Kinetic characterization of a saturable pathway for rapid clearance of circulating fibrin monomer. Blood 65:680-8 |
