Abstract
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder limited to the lung. New findings, starting from our proteomics studies on IPF, suggest that systemic involvement with altered molecular mechanisms and metabolic disorder is an underlying cause of fibrosis. The role of metabolic dysregulation in the pathogenesis of IPF has not been extensively studied, despite a recent surge of interest. In particular, our studies on bronchoalveolar lavage fluid have shown that the renin–angiotensin–aldosterone system (RAAS), the hypoxia/oxidative stress response, and changes in iron and lipid metabolism are involved in onset of IPF. These processes appear to interact in an intricate manner and to be related to different fibrosing pathologies not directly linked to the lung environment. The disordered metabolism of carbohydrates, lipids, proteins and hormones has been documented in lung, liver, and kidney fibrosis. Correcting these metabolic alterations may offer a new strategy for treating fibrosis. This paper focuses on the role of metabolic dysregulation in the pathogenesis of IPF and is a continuation of our previous studies, investigating metabolic dysregulation as a new target for fibrosis therapy.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a severe chronic interstitial lung disease (ILD) of unknown aetiology [1], limited to the lungs
The dysregulation of calgranulin A8 (S100A8), A1AT and ALBU suggests “IL-12 signalling and production in macrophages” and the “production of nitric oxide and reactive oxygen species in macrophages”, stressing the role of macrophages in acute exacerbation [20]. Another proteomic study by Landi et al on the bronchoalveolar lavage (BAL) of patients with pulmonary fibrosis related to systemic sclerosis showed the dysregulation of proteins related to lipid metabolism, such as lysozyme C, fatty acid binding protein 4 (FABP4), retinol binding protein 4 (RBP4) and HP, functionally correlated with PPAR-γ, underlining the idea of lipid metabolic alterations concomitant with the onset and development of fibrosis [45]
RBP4, another protein that we found dysregulated in BAL samples, is a cytokine primarily produced by adipose tissue and connected to PPAR-γ
Summary
Idiopathic pulmonary fibrosis (IPF) is a severe chronic interstitial lung disease (ILD) of unknown aetiology [1], limited to the lungs. Our research group applied proteomic methods to the bronchoalveolar lavage (BAL) fluid of IPF patients, observing the alteration of certain molecular mechanisms linked to metabolism and fibrosis [17,18,19,20,21]. These alterations concerned the renin–angiotensin–aldosterone system, hypoxia and oxidative stress, endoplasmic reticulum (ER) stress, lipid metabolism and iron metabolism. We focus on these aspects in the present paper, in particular on the role of metabolic dysregulation in the pathogenesis of IPF
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