Targeting the Apoptosis-Resistant Pulmonary Myofibroblast

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an incurable fatal disease with increasing incidence and mortality. Despite recent coordinated attempts to rapidly translate findings which have been validated in vitro and in preclinical models into biologically promising interventions, there have been no major therapeutic breakthroughs. A final common pathway for the destructive remodeling which characterizes fibrosis is the apoptosis-resistant myofibroblast, which both creates and responds to an altered mediator and matrix microenvironment, thus perpetuating fibrogenesis. Halting the development of the myofibroblast phenotype, or reversing it once established, offers the best hope of successfully treating IPF. The cell surface glycoprotein Thy-1, a known tumor suppressor which acts as a context-dependent regulator of cell phenotype, is silenced in the myofibroblasts within fibroblastic foci, the signature histopathologic lesions in IPF, the presence of which portends a poor prognosis. Absence of Thy-1 in cultured lung fibroblasts promotes proliferation, cytokine and growth factor expression and responsiveness, migration, myofibroblastic differentiation, and resistance to apoptosis, all reversible upon re-expression of Thy-1. Thy-1 interacts with alpha v integrins and syndecan 4 at the cell surface, modulating cell-cell and cell-matrix interactions and mechanical coupling, to inhibit TGF-beta activation and myofibroblastic differentiation. The effects of Thy-1 on the myofibroblast phenotype are broad, including: decreased expression of a number of muscle-specific proteins and myogenic transcription factors, inhibition of contractility, and promotion of apoptosis. Furthermore, some of the functions of Thy-1 can be recapitulated by the administration of soluble Thy-1, and preliminary data demonstrate that soluble Thy-1 reverses established fibrosis in a mouse model, indicating that Thy-1 itself can be used or modified for therapeutic benefit. Taken together, this knowledge leads us to the overall hypothesis that Thy-1-mediated signaling broadly suppresses myofibroblastic transformation and promotes apoptosis, restoring homeostatic function in lung fibroblasts. Improved understanding of the molecular mechanisms involved will uncover novel strategies for reversing the pathogenic myofibroblast phenotype in IPF and other fibrotic disorders. In vitro and in vivo models based on heterogeneity and targeted disruption of Thy-1 offer excellent opportunities for defining myofibroblast-targeting strategies, as outlined in the following specific aims: Aim 1: To define the mechanisms by which Thy-1- inhibits myofibroblastic differentiation of lung fibroblasts; Aim 2: To define the mechanisms by which Thy-1 promotes myofibroblast apoptosis; and Aim 3: To harness Thy-1-modulated signaling to reverse the apoptosis-resistant myofibroblast phenotype in vivo. Significance: Because Thy-1 modulates multiple signaling pathways critical to fibrogenesis, capitalizing on its function is more attractive than targeting a single pathway, which has been shown to be an ineffective approach in IPF. The proposed studies will thus define mechanisms by which Thy-1 suppresses profibrotic differentiation of lung fibroblasts, and translate that knowledge into innovative therapeutic interventions for fibrotic lung disease.