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.

Background Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS. Results Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS Ap3b1 gene mutation. Moreover, immunohistochemical staining localized this increase in MMP expression to the distal pulmonary epithelium, and shRNA knockdown of the Ap3b1 gene in cultured lung epithelial cells resulted in a similar upregulation in MMP-2 and -9 expression. Mechanistically, we found that upregulation in MMP expression associated with increased activity of the serine/threonine kinase Akt, and pharmacological inhibition of this enzyme resulted in a dramatic suppression of MMP expression in Ap3b1 deficient lung epithelial cells. Similarly, levels and activity of different MMPs were also found to be increased in the lungs of mice carrying the Bloc3 HPS gene mutation and in the bronchoalveolar lavage fluid of subjects with HPS. However, an association between MMP activity and disease severity was not detected in these individuals. Conclusions In summary, our findings indicate that MMP activity is dysregulated in the HPS lung, suggesting a role for these proteases as biological markers or pathogenic players in HPS lung disease. Electronic supplementary material The online version of this article (10.1186/s13023-019-1143-0) contains supplementary material, which is available to authorized users.

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Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.