Metabolic Reprogramming as a Driver of Fibroblast Activation in PulmonaryFibrosis

Abstract

Pulmonary fibrosis refers to a heterogeneous group of disorders that scar the lung, most often irreversibly. To date, there are limited effective treatments for these conditions, despite decades of research in this area of investigation. In pulmonary fibrosis, the principle cell responsible for producing the vast majority of scar tissue is the fibroblast, making these cells ideally suited for drug targeting. For decades, the major experimental approach to blocking the activity of lung fibroblasts has been either to inhibit the interaction of fibroblast growth factors with their receptors or interfere with downstream effector molecules regulating extracellular matrix production. However, emerging evidence now indicates that lung fibroblasts also undergo dramatic metabolic reprogramming in the setting of growth factor stimulation. These discoveries, along with preclinical investigations showing marked reductions in lung fibrosis after targeting specific metabolic pathways, has led to a total rethinking of drug development in the pulmonary fibrosis field. Here, we review the major metabolic pathways and highlight some of the key metabolic events that occur in the transition of fibroblasts from quiescent to activated states. Moreover, we discuss the emerging evidence linking changes in fibroblast metabolism to pulmonary fibrosis and propose how targeting specific metabolic pathways could be employed in the treatment of fibrotic lung diseases.

TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts

“…Although it has long been recognized that alterations in cellular metabolism play an essential role in helping tumour cells acquire and maintain their malignant properties, we are starting to appreciate that cellular metabolism is altered in many forms of disease. Of particular interest is the observation that in various organs, fibroblasts undergo dramatic metabolic reprogramming during activation to facilitate growth, proliferation and their synthetic activities 6 , 7 , 9 , 10 , 35 . In some respects this resembles the so-called Warburg effect seen in tumours, where there is a shift from oxidative phosphorylation to aerobic glycolysis to support hyper-proliferation and protein synthesis 4 .…”

“…More recently we have also seen that metabolic reprograming plays an essential role in the differentiation and cell fate commitment of pluripotent stem cells 5 . Likewise there is also mounting evidence of a reprogramming of cellular metabolism in various forms of fibrosis [6][7][8] , including myofibroblast-like cells 8,9 in keloids 10 , hepatic 11,12 , lung 8 and perioteneal 13 fibrosis. Although TGF-β1 is a specific driver in many cases [11][12][13] , the molecular events underpinning these global changes remain ill-defined.…”

Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

“…For instance, it has been acknowledged that fibroblasts can play a significant role in disease pathogenesis by presenting complex phenotypes and functions according to the biological context. Indeed, some fibroblasts (e.g., gingival [ 7 ], dermal [ 8 ], lung [ 9 ], cardiac [ 10 ] and synovial fibroblasts [ 11 ]) can express innate immune receptors to sense pathogens and present antigens, contributing to the immune response [ 12 ].…”

Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms using Computational Systems Biology Approaches

“…Indeed, some fibroblasts (e.g. gingival [7], dermal [8], lung [9], cardiac [10] and synovial fibroblasts [11]) can express innate immune receptors to sense pathogens and present antigens, contributing to the immune response [12]. However, relatively few studies have…”