Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis

Little is known about the pathobiology of acute exacerbation of idiopathic pulmonary fibrosis (IPF), a condition that shares clinical and histopathological features with acute lung injury. Plasma biomarkers have been well studied in acute lung injury and have provided insight into the underlying disease mechanism. The objective of this study was to determine the plasma biomarker profile of acute exacerbation of IPF and compare this profile with that of stable IPF and acute lung injury. Plasma was collected from patients with stable IPF, acute exacerbation of IPF, and acute lung injury for measurement of biomarkers of cellular activity/injury (receptor for advanced glycation endproducts, surfactant protein D, KL-6, von Willebrand factor), systemic inflammation (IL-6), and coagulation/fibrinolysis (protein C, thrombomodulin, plasminogen activator inhibitor-1). Plasma from patients with acute exacerbation of IPF showed significant elevations in markers of type II alveolar epithelial cell injury and/or proliferation, endothelial cell injury, and coagulation. This profile differed from the biomarker profile in patients with acute lung injury. These findings support the hypothesis that type II alveolar epithelial cells are centrally involved in the pathobiology of acute exacerbation of IPF. Furthermore, they suggest that acute exacerbation of IPF has a distinct plasma biomarker profile from that of acute lung injury.

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Acute Exacerbations In Idiopathic Pulmonary Fibrosis Are Associated With Pulmonary Hypertension And Histological Acute Lung Injury In Explanted IPF Tissue

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2498 ◽

2010 ◽

Author(s):

Eoin P. Judge ◽

Aurelie Fabre ◽

Jim McCarthy ◽

A. E. Wood ◽

Jim J. Egan

Keyword(s):

Pulmonary Hypertension ◽

Acute Lung Injury ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Acute Exacerbations

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Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00489.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L1-L11 ◽

Cited By ~ 26

Author(s):

Margaret K. Winkler ◽

John L. Fowlkes

Keyword(s):

Acute Lung Injury ◽

Growth Factors ◽

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

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Fibrotic expression profile analysis reveals repurposed drugs with potential anti-fibrotic mode of action

PLoS ONE ◽

10.1371/journal.pone.0249687 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249687

Author(s):

Evangelos Karatzas ◽

Andrea C. Kakouri ◽

George Kolios ◽

Alex Delis ◽

George M. Spyrou

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Profile Analysis ◽

Oral Submucous Fibrosis ◽

Drug Repurposing ◽

Biological Pathways ◽

Igg4 Related Disease ◽

Submucous Fibrosis ◽

Repurposed Drugs ◽

Fibrotic Diseases

Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis, an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target. In this study we highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among 9 fibrotic diseases. We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our Drug Repurposing results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis. We suggest digoxin to be tested against Oral Submucous Fibrosis, since we observe cardiomyopathy-related pathways implicated in Oral Submucous Fibrosis and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that Idiopathic Pulmonary Fibrosis shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren’s Disease, IgG4-related Disease, Systemic Sclerosis and Cystic Fibrosis. We propose that treatments for these fibrotic diseases should be jointly pursued.

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