scholarly journals A validated hypoxia-inducible factor (HIF) signature across tissue compartments predicts clinical outcome in human lung fibrosis

2022 ◽  
Author(s):  
Yilu Zhou ◽  
Rob Ewing ◽  
Donna E. Davies ◽  
Yihua Wang ◽  
Mark Jones
Keyword(s):  
Oxidative Stress ◽  
Lung Fibrosis ◽  
Mononuclear Cells ◽  
Human Lung ◽  
Hypoxia Inducible Factor ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Pathway Activation ◽  
Tissue Compartments ◽  
Hif Pathway

We previously reported that oxidative stress drives pseudohypoxic hypoxia-inducible factor (HIF) pathway activation to promote pathogenetic collagen structure-function in human lung fibrosis (Brereton et al., 2022). Here, through bioinformatic studies we investigate HIF pathway activation status in patients with idiopathic pulmonary fibrosis (IPF) and whether this has prognostic significance. Applying a well-established HIF gene expression signature, we classified publicly available datasets into HIF score-high and score-low groups across multiple tissue compartments. TheHIF scores in lung tissue, bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMC) were increased in IPF patients and significantly correlated with an oxidative stress signature consistent with pseudohypoxic HIF pathway activation. A high HIF score in BAL and in PBMC was a strong independent predictor of mortality in multivariate analysis. Thus, a validated HIF gene signature predicts survival across tissue compartments in IPF and merits prospective study as a non-invasive biomarker of lung fibrosis progression.

scholarly journals Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

2021 ◽  
Author(s):  
Christopher J Brereton ◽  
Liudi Yao ◽  
Yilu Zhou ◽  
Milica Vukmirovic ◽  
Joseph A Bell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Structure Function ◽  
Lung Fibrosis ◽  
Human Lung ◽  
Ex Vivo ◽  
Fibrillar Collagen ◽  
Collagen Structure ◽  
Critical Pathway ◽  
Pathway Activation ◽  
Hif Pathway

Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGFβ increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting 'bone-type' cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen-structure function in fibrosis.

scholarly journals Molecular Assessment of Epiretinal Membrane: Activated Microglia, Oxidative Stress and Inflammation

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 654 ◽  
Author(s):  
Sushma Vishwakarma ◽  
Rishikesh Kumar Gupta ◽  
Saumya Jakati ◽  
Mudit Tyagi ◽  
Rajeev Reddy Pappuru ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Epiretinal Membrane ◽  
Hypoxia Inducible Factor ◽  
Gene Expression Signature ◽  
Cell Types ◽  
Activated Microglia ◽  
Inflammatory Conditions ◽  
New Information ◽  
And Function

Fibrocellular membrane or epiretinal membrane (ERM) forms on the surface of the inner limiting membrane (ILM) in the inner retina and alters the structure and function of the retina. ERM formation is frequently observed in ocular inflammatory conditions, such as proliferative diabetic retinopathy (PDR) and retinal detachment (RD). Although peeling of the ERM is used as a surgical intervention, it can inadvertently distort the retina. Our goal is to design alternative strategies to tackle ERMs. As a first step, we sought to determine the composition of the ERMs by identifying the constituent cell-types and gene expression signature in patient samples. Using ultrastructural microscopy and immunofluorescence analyses, we found activated microglia, astrocytes, and Müller glia in the ERMs from PDR and RD patients. Moreover, oxidative stress and inflammation associated gene expression was significantly higher in the RD and PDR membranes as compared to the macular hole samples, which are not associated with inflammation. We specifically detected differential expression of hypoxia inducible factor 1-α (HIF1-α), proinflammatory cytokines, and Notch, Wnt, and ERK signaling pathway-associated genes in the RD and PDR samples. Taken together, our results provide new information to potentially develop methods to tackle ERM formation.

scholarly journals HIF Pathways in Clear Cell Renal Cancer

2021 ◽  
Author(s):  
Olivia Lombardi ◽  
David Robert Mole
Keyword(s):  
Cell Proliferation ◽  
Clear Cell ◽  
Hypoxia Inducible Factor ◽  
Von Hippel Lindau ◽  
Pathway Activation ◽  
Cellular Energetics ◽  
Cellular Oxygen ◽  
Immune Destruction ◽  
Hif Pathway ◽  
Cell Renal Cancer

Clear cell renal cancers (ccRCC) are characterized by inactivation of the VHL (von Hippel–Lindau) tumor suppressor. Work leading to the 2019 Nobel Prize for Physiology or Medicine has shown that this is central to cellular oxygen-sensing, orchestrated by the HIF (hypoxia-inducible factor) transcription factors. These regulate hundreds of genes that underpin many hallmarks of cancer, including angiogenesis, cellular energetics, cell proliferation, resisting cell death, and avoiding immune destruction. However, HIF also promotes processes that are detrimental to cancer cells. Therefore, the overall consequence of HIF pathway activation is a balance of these influences. We explore how variations in the HIF pathway during tumorigenesis alter this balance to promote ccRCC formation.

HIF pathway activation is a core regulator of collagen structure-function in lung fibrosis

2020 ◽  
Author(s):  
Christopher J Brereton ◽  
Robert Ridley ◽  
Franco Conforti ◽  
Liudi Yao ◽  
Aiman Alzetani ◽  
...  
Keyword(s):  
Structure Function ◽  
Lung Fibrosis ◽  
Collagen Structure ◽  
Pathway Activation ◽  
Hif Pathway

scholarly journals Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

2021 ◽  
Vol 16 (1) ◽  
pp. 537-543
Author(s):  
Mei Zhang ◽  
Jing Yuan ◽  
Rong Dong ◽  
Jingjing Da ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Injury ◽  
Jnk Pathway ◽  
Pathway Activation

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

scholarly journals Hypoxia-Inducible Factor 2a Expression Is Positively Correlated With Gleason Score in Prostate Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382199001
Author(s):  
Dimitrios Pavlakis ◽  
Spyridon Kampantais ◽  
Konstantinos Gkagkalidis ◽  
Victoras Gourvas ◽  
Dimitrios Memmos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Locally Advanced ◽  
Hypoxia Inducible Factor ◽  
Immunohistochemical Expression ◽  
Locally Advanced Prostate Cancer ◽  
Grade Group ◽  
Main Factors ◽  
Hif Pathway ◽  
Lower Expression

Background: One of the main factors in response to hypoxia in the tumor microenvironment is the hypoxia-inducible factor (HIF) pathway. Although its role in other solid tumors, particularly renal cell carcinoma, has been sufficiently elucidated, it remains elusive in prostate cancer. The aim of the present study was to investigate the expression of main proteins involved in this pathway and determine the correlation of the results with clinicopathological outcomes of patients with prostate cancer. Methods: The immunohistochemical expression of HIF-1a, HIF-2a and their regulators, prolyl hydroxylase domain (PHD)1, PHD2 and PHD3 and factor inhibiting HIF (FIH), was assessed on a tissue microarray. This was constructed from radical prostatectomy specimens, involving both tumor and corresponding adjacent non-tumoral prostate tissues from 50 patients with localized or locally advanced prostate cancer. Results: In comparison with non-tumoral adjacent tissue, HIF-1a exhibited an equal or lower expression in 86% of the specimens (P = 0.017), while HIF-2a was overexpressed in 52% (P = 0.032) of the cases. HIF-1a protein expression was correlated with HIF-2a (P < 0.001), FIH (P = 0.004), PHD1 (P < 0.001), PHD2 (P < 0.001) and PHD3 (P = 0.035). HIF-2a expression was positively correlated with Gleason score (P = 0.017) and International Society of Urological Pathologists (ISUP) grade group (P = 0.022). Conclusions: The findings of the present study suggest a key role for HIF-2a in prostate cancer, as HIF-2a expression was found to be correlated with Gleason score and ISUP grade of the patients. However, further studies are required to validate these results and investigate the potential value of HIF-2a as a therapeutic target in prostate cancer.

Sign in / Sign up

Export Citation Format

Share Document