Tissue stiffness promotes pro-fibrotic metabolic dysregulation in lung fibrosis

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PROJECT SUMMARY/ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease of the lung with a median survival rate shorter than lung cancer. Current treatments slow disease progression in some patients but are not a cure. IPF and other forms of interstitial lung disease are characterized by an accumulation of excess extracellular matrix (ECM), contributing to the destruction of lung architecture, inability to perform gas exchange, and eventually death. We published pioneering work that IPF patients have abnormally high levels of lactate in their lungs, and that TGFβ drives fibroblasts to produce excess lactate in culture. Lactate in turn decreases the local pH, which activates latent TGFβ resulting in a pro-fibrotic feed-forward loop, driving fibrosis. We, as well as other laboratories have published research into the pro-fibrotic properties of ECM and ECM-modifying enzymes. Briefly, TGFβ drives excess deposition of ECM proteins by fibroblasts and myofibroblasts, and increases crosslinking of the ECM, stiffening the ECM. Tissue stiffening is a hallmark of fibrotic disorders and has been marked as an outcome of fibrosis. Now, we recognize that high stiffnesses of the fibrotic lung directly induces myofibroblast differentiation and pro-fibrotic gene expression, at least partly by activating latent TGFβ via mechanical forces involving integrins and other cell surface proteins. This creates a second pro-fibrotic feed- forward loop where fibroblasts in a stiff microenvironment are driven toward a fibrotic phenotype that increases the stiffness of the microenvironment. The importance of metabolic dysregulation and tissue stiffness in pulmonary fibrosis have been studied in isolation, but the potential links between these two key pathways have not been studied. The interconnections between these two pathways may help to explain why monotherapies that target single pathways have shown only limited success. Here, we will investigate for the first time, the proposition that the mechanical stress pathways, and metabolic dysregulation pathways that promote fibrosis are interconnected, and that biomechanical stress drives normal lung fibroblasts toward a pro-fibrotic phenotype in part by driving metabolic changes resulting in excess production of lactate and activation of TGFβ . Our overall hypothesis is that altered tissue stiffness enhances dysregulation of lactate metabolism and contributes to myofibroblast differentiation and pulmonary fibrosis, and that combinatorial pharmacologic inhibition of matrix crosslinking and dysregulated lactate metabolism represents a novel therapeutic strategy to restore homeostasis in an otherwise devastating disease. We will evaluate several existing and novel therapeutic approaches to slow, prevent or reverse fibrotic changes in lung cells and in a preclinical mouse model of pulmonary fibrosis, to determine if interfering in mechanical stress and metabolic pathways can slow or halt disease progression.