scholarly journals Glutaminolysis Epigenetically Regulates Antiapoptotic Gene Expression in Idiopathic Pulmonary Fibrosis Fibroblasts

2019 ◽  
Vol 60 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Le Bai ◽  
Karen Bernard ◽  
Xuebo Tang ◽  
Min Hu ◽  
Jeffrey C. Horowitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Antiapoptotic Gene

scholarly journals Itaconate controls the severity of pulmonary fibrosis

2020 ◽  
Vol 5 (52) ◽  
pp. eabc1884 ◽  
Author(s):  
Patricia P. Ogger ◽  
Gesa J. Albers ◽  
Richard J. Hewitt ◽  
Brendan J. O’Sullivan ◽  
Joseph E. Powell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Therapeutic Strategy ◽  
Lung Fibroblasts ◽  
Disease Phenotype ◽  
Wild Type

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1−/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1−/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

scholarly journals Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis

2016 ◽  
Vol 310 (10) ◽  
pp. L940-L954 ◽  
Author(s):  
Irina G. Luzina ◽  
Virginia Lockatell ◽  
Sang W. Hyun ◽  
Pavel Kopach ◽  
Phillip H. Kang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Recombinant Adenovirus ◽  
Global Gene Expression

Idiopathic pulmonary fibrosis (IPF) poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins. We observed increased NEU1 expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of NEU1 to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. NEU1 overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of NEU1 encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-β and collagen. The lymphocytes were predominantly T cells, with CD8+ cells exceeding CD4+ cells by nearly twofold. These combined data indicate that elevated NEU1 expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung fibrosis.

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