Understanding the role of the immune system in progression of fibrosis


   Institute of Inflammation and Ageing

  Dr A Scott, Dr D Parekh  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The pathogenic mechanism of pulmonary fibrosis (PF) is still not well understood. Initially believed to be a side effect of dysregulated inflammatory processes as the main driver, data now appears not to support this. Recent data supports the epithelial injury-dysfunctional fibroblasts axis.

In this model repeated injury to the alveolar epithelium and endothelium results in granulomatous inflammation, excessive cell death. dysfunctional regenerative/repair processes, excess collagen deposition and exaggerated growth factor release. It is also generally accepted fibroblasts are the main drivers of lung fibrosis. Given the classically accepted model of PF is not associated with high levels of inflammation, the role of immune cells is somewhat under-investigated,

Ageing is the main risk factor for fibrotic lung disease. At a cellular level this is characterised by loss of regenerative capacity, accumulation of epigenetic changes, mitochondrial dysfunction, senescence and dysregulated redox balance/increased oxidant load. Each of these factors has been tied to increased risk of fibrosis individually and in combination.

Chronic hypoxia is also known to worsen fibrotic conditions throughout the body and particular the pathways associated with hypoxia are upregulated in fibrotic lung disease. Histological studies on fibrotic areas of IPF lung tissue and murine models of bleomycin lung injury show markers of hypoxia including increased hypoxia inducible factor 1 alpha (HIF-1α) expression

We propose that senesce driven through the master regulator of HIF-1α, to drive fibrosis through both localised to the hypoxic-immune cell microenvironment within the lung, the oxygen sensitive activation of the HIF-1α pathway, and through non-oxygen sensitive activators of the HIF-1α pathway such as UMP, LPS and ROS.

Further defining the complex interplay of mesenchymal and immune cells within the fibrotic lung using ex vivo primary cell models and tissue models such as the precision cut lung slice model will give us greater insight into possible new intervention points for development of novel therapeutics.  

Person Specification

Applicants should have a strong background in Biomedical science, and ideally a background in molecular biology. They should have a commitment to research in Respiratory science and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply

Informal enquiries should be directed to Aaron Scott and Dhruv Parekh

Applications should be directed to Aaron Scott and Dhruv Parekh (email and ). To apply, please send:

•          A detailed CV, including your nationality and country of birth;

•          Names and addresses of two referees;

•          A covering letter highlighting your research experience/capabilities;

•          Copies of your degree certificates with transcripts;

•          Evidence of your proficiency in the English language, if applicable.

Biological Sciences (4)

Funding Notes

Funding availability: Self-funded PhD students will be considered for this project.

References

1. Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. European respiratory review : an official journal of the European Respiratory Society 2015; 24: 102-114.
2. Zaman T, Lee JS. Risk factors for the development of idiopathic pulmonary fibrosis: A review. Curr Pulmonol Rep 2018; 7: 118-125.
3. Epstein Shochet G, Bardenstein-Wald B, McElroy M, Kukuy A, Surber M, Edelstein E, Pertzov B, Kramer MR, Shitrit D. Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis. Int J Mol Sci 2021; 22.
4. Xiong A, Liu Y. Targeting Hypoxia Inducible Factors-1α As a Novel Therapy in Fibrosis. Front Pharmacol 2017; 8: 326.
5. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 2005; 105: 659-669.
6. Mingyuan X, Qianqian P, Shengquan X, Chenyi Y, Rui L, Yichen S, Jinghong X. Hypoxia-inducible factor-1α activates transforming growth factor-β1/Smad signaling and increases collagen deposition in dermal fibroblasts. Oncotarget 2018; 9: 3188-3197.
7. Khawaja AA, Chong DLW, Sahota J, Mikolasch TA, Pericleous C, Ripoll VM, Booth HL, Khan S, Rodriguez-Justo M, Giles IP, Porter JC. Identification of a Novel HIF-1α-α(M)β(2) Integrin-NET Axis in Fibrotic Interstitial Lung Disease. Front Immunol 2020; 11: 2190.
8. Richter AG, Perkins GD, Chavda A, Sapey E, Harper L, Thickett DR. Neutrophil chemotaxis in granulomatosis with polyangiitis (Wegener's) and idiopathic pulmonary fibrosis. The European respiratory journal 2011; 38: 1081-1088.

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