Abstract
Pulmonary fibrosis is a chronic and progressive lung disease characterized by the activation of fibroblasts and the irreversible deposition of connective tissue matrices that leads to altered pulmonary architecture and physiology. Multiple factors have been implicated in the pathogenesis of lung fibrosis, including genetic and environmental factors that cause abnormal activation of alveolar epithelial cells, leading to the development of complex profibrotic cascade activation and extracellular matrix (ECM) deposition. One class of proteinases that is thought to be important in the regulation of the ECM are the matrix metalloproteinases (MMPs). MMPs can be up- and down- regulated in idiopathic pulmonary fibrosis (IPF) lungs and their role depends upon their location and function. Furthermore, alterations in the ubiquitin-proteosome system (UPS), a major intracellular protein degradation complex, have been described in aging and IPF lungs. UPS alterations could potentially lead to the abnormal accumulation and deposition of ECM. A better understanding of the specific roles MMPs and UPS play in the pathophysiology of pulmonary fibrosis could potentially drive to the development of novel biomarkers that can be as diagnostic and therapeutic targets. In this review, we describe how MMPs and UPS alter ECM composition in IPF lungs and mouse models of pulmonary fibrosis, thereby influencing the alveolar epithelial and mesenchymal cell behavior. Finally, we discuss recent findings that associate MMPs and UPS interplay with the development of pulmonary fibrosis.
Highlights
Pulmonary fibrosis refers to a group of conditions that cause scarring of the lung
Our study showed that HPS2-mice had elevated transcript levels of MMP2 and MMP9, while broad upregulation of MMP2, -3, -8, -9, -12, and -14 transcripts was evidenced in the HPS1-mice, suggesting that the pathogenesis of pulmonary fibrosis might differ in the different Hermanksy-Pudlak Syndrome (HPS) mutations
Akt activity has been shown to be upregulated in alveolar epithelial type 2 (AE2) cells of idiopathic pulmonary fibrosis (IPF) lungs, supporting the notion that targeting Akt might represent a therapeutic approach in HPS and IPF [52] (Figure 1)
Summary
Pulmonary fibrosis refers to a group of conditions that cause scarring of the lung. It is estimated that these conditions represent 10% of all visits to subspecialty pulmonary clinics, making fibrotic lung conditions one of the major causes of morbidity and mortality from respiratory illness. Unlike idiopathic pulmonary fibrosis (IPF), the etiology of HPS is known, as this condition results from autosomal recessive mutations in one of 10 lysosomal trafficking proteins Despite these differences, the pathologic changes in pulmonary fibrosis in HPS is nearly indistinguishable from IPF, exhibiting similar lung fibroblast activation and exaggerated accumulation of extracellular matrix (ECM) components such as collagens and fibrins [4]. The pathologic changes in pulmonary fibrosis in HPS is nearly indistinguishable from IPF, exhibiting similar lung fibroblast activation and exaggerated accumulation of extracellular matrix (ECM) components such as collagens and fibrins [4] These pathologic changes are likely due to protease dysregulation, matrix metalloproteinases and the ubiquitin proteasome system, leading to the protein aggregation evidenced in these diseases. This review explores the main aspects of MMPs and UPS regulation, the evidence establishing an inter-play between these two, their role in the pathogenesis of pulmonary fibrosis and potential therapeutic targets for this devastating disease
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