Idiopathic Pulmonary Fibrosis (IPF) is a fibrotic lung disease characterized by the accumulation of activated mesenchymal cells (myofibroblasts) within subepithelial clusters called fibroblastic foci. The abundance of these fibroblastic foci correlates with the dismal prognosis of this disease, which has a median survival of only 2-3 years. No pharmacologic intervention has improved survival for patients with IPF, and there is an urgent need for novel and efficacious therapies to treat this disease. IPF pathogenesis involves a dysfunctional response to chronic/recurrent alveolar epithelial injury. Increased lung stiffness is a physiologic correlate of pulmonary fibrosis that has been thought to result from myofibroblast accumulation and excessive deposition of extracellular matrix (ECM). Calling this paradigm of fibrogenesis into question, recent studies show that increased tissue stiffness precedes myofibroblast accumulation and matrix production in liver fibrosis. These findings suggest that increased tissue stiffness may not be a simple consequence of fibrosis; it may directly contribute to fibrogenesis. Prior studies of the myofibroblast fate regulation, however, have focused on the effects of soluble mediators (transforming growth factor beta-1 and endothelin-1), using rigid plastic substrates with supra-physiologic stiffness. The role of mechanotransduction in the regulation of myofibroblast fate is not known, and the mechanisms by which biomechanical signals from the ECM modulate biochemical signals from soluble factors to regulate fibroblast survival/apoptosis are poorly understood. Focal adhesion kinase (FAK) is an integral component of mechanotransduction signaling that is critical for the maintenance of myofibroblast survival. FAK is increased in fibrotic lungs, and inhibition of FAK attenuates bleomycin-induced fibrosis in mice. Moreover, plasmin-mediated ECM proteolysis, which induces myofibroblast apoptosis, is associated with the loss of FAK activity. The central role of FAK in pulmonary fibrosis and in the regulation of myofibroblast survival motivates our central hypothesis that mechanical signals associated with increased lung parenchymal stiffness are critical for mesenchymal cell resistance to apoptosis and, therefore, the pathogenesis of pulmonary fibrosis.
The specific aims of this proposal are to (1) determine the mechanisms by which substrates with physiologic and pathologic stiffness differentially regulate mesenchymal cell apoptosis; (2) define how mechanical stimuli modulate the effects of soluble mediators on mesenchymal cell apoptosis; and (3) determine the relationship between lung compliance, fibrogenesis, and mesenchymal cell accumulation. The proposed studies will enhance our fundamental understanding of myofibroblast fate regulation in physiologic and pathologic wound healing and facilitate identification of novel anti-fibrotic targets for intervention in pulmonary fibrosis.
The proposed studies will enhance our fundamental understanding of myofibroblast fate regulation in physiologic and pathologic wound healing and facilitate identification of novel anti-fibrotic targets for intervention in pulmonary fibrosis.
| Horowitz, Jeffrey C (2018) Investigating Matrix-Fibroblast Regulation of MicroRNAs. A Dice(r)y Proposition. Am J Respir Crit Care Med 198:418-419 |
| Dodi, Amos E; Ajayi, Iyabode O; Chang, Christine et al. (2018) Regulation of fibroblast Fas expression by soluble and mechanical pro-fibrotic stimuli. Respir Res 19:91 |
| Zhou, Yong; Horowitz, Jeffrey C; Naba, Alexandra et al. (2018) Extracellular matrix in lung development, homeostasis and disease. Matrix Biol 73:77-104 |
| Kim, Kevin K; Sisson, Thomas H; Horowitz, Jeffrey C (2017) Fibroblast growth factors and pulmonary fibrosis: it's more complex than it sounds. J Pathol 241:6-9 |
| Horowitz, Jeffrey C (2017) Releasing Tensin. Am J Respir Cell Mol Biol 56:417-418 |
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| Wheaton, Amanda K; Velikoff, Miranda; Agarwal, Manisha et al. (2016) The vitronectin RGD motif regulates TGF-?-induced alveolar epithelial cell apoptosis. Am J Physiol Lung Cell Mol Physiol 310:L1206-17 |
| Chanda, Diptiman; Kurundkar, Ashish; Rangarajan, Sunad et al. (2016) Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis. Sci Rep 6:37445 |
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