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 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 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 Structure-Function Analysis of Grass Clip Serine Protease Involved inDrosophilaToll Pathway Activation

2011 ◽  
Vol 286 (14) ◽  
pp. 12300-12307 ◽  
Author(s):  
Christine Kellenberger ◽  
Philippe Leone ◽  
Laurent Coquet ◽  
Thierry Jouenne ◽  
Jean-Marc Reichhart ◽  
...  
Keyword(s):  
Structure Function ◽  
Serine Protease ◽  
Function Analysis ◽  
Pathway Activation

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.

scholarly journals Collagen – structure, function and distribution in orodental tissues

2020 ◽  
Vol 2 ◽  
pp. 134-139
Author(s):  
Zaneta D’souza ◽  
Tabita Joy Chettiankandy ◽  
Manisha S. Ahire (Sardar) ◽  
Arush Thakur ◽  
Sarang G. Sonawane ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Adhesion ◽  
Structure Function ◽  
Large Family ◽  
The Body ◽  
Collagen Structure ◽  
Basic Framework ◽  
Helical Proteins ◽  
And Function

Collagens are a large family of triple helical proteins which are found extensively throughout the body. They form the basic framework of the extracellular matrix providing support and form to cells and tissues. They are important for various functions such as angiogenesis, morphogenesis, cell adhesion, repair, and regeneration. In this article, we have focused our discussion to the structure, the synthesis, and the degradation of collagen followed by its distribution and function in various oral tissues.

scholarly journals Collagen Structure-Function Mapping Informs Applications for Regenerative Medicine

2020 ◽  
Vol 8 (1) ◽  
pp. 3
Author(s):  
James D. San Antonio ◽  
Olena Jacenko ◽  
Andrzej Fertala ◽  
Joseph P.R.O. Orgel
Keyword(s):  
Structure Function ◽  
Cancer Metastasis ◽  
Type I Collagen ◽  
Tissue Injury ◽  
Tissue Remodeling ◽  
Type Iii Collagen ◽  
Type I ◽  
Collagen Structure ◽  
Interaction Domain ◽  
Functional Sites

Type I collagen, the predominant protein of vertebrates, assembles into fibrils that orchestrate the form and function of bone, tendon, skin, and other tissues. Collagen plays roles in hemostasis, wound healing, angiogenesis, and biomineralization, and its dysfunction contributes to fibrosis, atherosclerosis, cancer metastasis, and brittle bone disease. To elucidate the type I collagen structure-function relationship, we constructed a type I collagen fibril interactome, including its functional sites and disease-associated mutations. When projected onto an X-ray diffraction model of the native collagen microfibril, data revealed a matrix interaction domain that assumes structural roles including collagen assembly, crosslinking, proteoglycan (PG) binding, and mineralization, and the cell interaction domain supporting dynamic aspects of collagen biology such as hemostasis, tissue remodeling, and cell adhesion. Our type III collagen interactome corroborates this model. We propose that in quiescent tissues, the fibril projects a structural face; however, tissue injury releases blood into the collagenous stroma, triggering exposure of the fibrils’ cell and ligand binding sites crucial for tissue remodeling and regeneration. Applications of our research include discovery of anti-fibrotic antibodies and elucidating their interactions with collagen, and using insights from our angiogenesis studies and collagen structure-function model to inform the design of super-angiogenic collagens and collagen mimetics.

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