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New insight opens path to tackle chronic lung disease

Updated: Apr 4, 2022


Southampton researchers have given new insight into the mechanisms of a chronic, progressive lung disease.


The understanding could help identify potential targets to improve treatment.


Idiopathic Pulmonary Fibrosis (IPF) is a serious condition in which the lungs become scarred.


The new study, published in eLife, has been driven by experts from the NIHR Southampton Biomedical Research Centre. It identified imbalances that affect collagen in the lungs and cause it to stiffen. This then triggers fibrosis progression over time.


Treating a chronic condition


IPF usually affects people who are around 70 to 75 years old. The condition causes difficulty breathing and symptoms tend to get slowly worse over time.


Mark Jones, Associate Professor in Respiratory Medicine and Honorary Consultant Respiratory Physician, said: “Patients with IPF survive between two to five years and so we need to develop new and improved treatments.


“We previously found that changes in collagen structure caused increased tissue stiffness and that this promoted fibrosis progression over time but we didn’t know why this was happening.

Our study has identified a key upstream pathway responsible for this and provides new understanding of how progressive fibrosis can be triggered.”


The research was co-led by Dr Jones as part of respiratory and allergy research in the NIHR Southampton Biomedical Research Centre (BRC).


The team involved the BRC’s Dr Chris Brereton as well as other researchers at Southampton, Yale, the University of Oxford, and University College Dublin.


Increasing tissue stiffness


Researchers analysed lung tissue from patients with IPF. They found that the two enzymes that modify collagen – PLOD2 and LOXL2 – were expressed in the same lung cells at the same time.


In lab experiments, they then found that a family of proteins called Hypoxia Inducible Factors (HIFs), which can regulate the body’s response to varying oxygen levels, activated the genes for PLOD2 and LOXL2.


This increased the number of cross-links between the collagen fibres and made the fibres stiffer. Using an electron microscope, they were able to see HIFs change the collagen’s structure.


Finally, they investigated what could be causing increased HIF activity in patients with IPF.


They identified that the presence of oxidative stress reduced activity of a protein called FIH (short for Factor Inhibiting HIF). Loss of FIH caused cells to enter ‘pseudohypoxia’, a state in which cells behave as if oxygen levels are low despite being in normal conditions. This led to higher levels of HIF activity, so altering collagen structure and increasing tissue stiffness.


Yihua Wang, Associate Professor from Biological Sciences who co-led the study, said: “These findings suggest that intervening at the level FIH or HIF could be better at treating IPF than targeting the machinery that synthesizes collagen, which is currently considered to be the most effective treatment approach. We are now investigating this new targeting approach.”


Image: Altered collagen (yellow) within human lung fibrosis tissue. Imaged by second harmonic generation.

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