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RESTENOSIS PATHOBIOLOGY--A CASCADE MECHANISM


Biography

Overview
Restenosis presently limits the long term success of coronary angioplasty (PTCA). It is unclear why thrombosis, often invoked as a cause of smooth muscle (SMC) proliferation, wanes before intimal thickening peaks and why prolonged anti-thrombotic therapy fails to eliminate restenosis post- PTCA. We propose that a cytokine-growth factor cascade contributes to restenosis: Acute local thrombosis and/or mechanical injury triggers initial cytokine gene expression by lesional macrophages and SMC. This acute generation of cytokines evokes a secondary growth factor and cytokine response establishing a positive, self-stimulatory, autocrine and paracrine feedback loop which amplifies and sustains SMC proliferation over time. This multistage schema would account for the lag between injury and restenosis, and failure of chronic antithrombotic therapy to eliminate this process.

1: We will test the hypothesis that balloon injury to an atheromatous artery acutely (4-24 h) activates endogenous mononuclear phagocytes as judged by local expression of cytokines such as IL1, M-CSF and MCP-1.

2: We will test the hypothesis that balloon injury to an atheromatous artery evokes delayed (>24 h) and continuing (1-28 d) local expression of endogenous cytokine and growth factor genes that may contribute to ongoing SMC proliferation and matrix production (e.g. rabbit IL1 isoforms, TNFalpha, PDGF A, FGFs, TGFbeta, and ICAM-1). We further hypothesize that the endothelium that covers previously ballooned areas will express a novel activation marker, athero-ELAM.

3: We will test our pathobiologic model by determining whether administration of selective inhibitors of thrombin or IL1 modulat the initiation or propagation of the proliferative response following balloon injury to atheromatous arteries. We will use hirudin or analogous peptides to inhibit thrombin and an IL1 receptor antagonist to inhibit IL1 action in rabbits. We will also explore other strategies for further dissection of the molecular and cellular response to balloon injury (e.g. neutralizing antibodies or local administration of antisense nucleic acid).

4: We will compare cytokine or growth factor mRNA and protein levels in human restenotic lesions compared with primary atheroma and normal vessels. We will test prospectively in patients undergoing atherectomy whether primary lesions initially richer in macrophages (as assessed by selective markers such as c-fms) have a greater propensity to develop restenosis.
R01HL047840
LIBBY, PETER

Time
1991-09-30
1995-07-31
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.