Understanding the mechanisms of Idiopathic Pulmonary Fibrosis (IPF)

Research from the Faculty of Medicine has given new insight into the mechanisms of Idiopathic Pulmonary Fibrosis (IPF), a serious condition in which the lungs become scarred and breathing becomes increasingly difficult.

The study, published in eLife , shows that oxidative stress alters the structure of collagen in the lungs which causes it to stiffen and that this promotes fibrosis progression over time.

The team believe the research could identify potential targets to improve treatment.

Mark Jones, Associate Professor in Respiratory Medicine, co-led the study and 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 team involved Dr Chris Brereton of the NIHR Southampton Biomedical Research Centre, Liudi Yao within Biological Sciences, as well as researchers at Yale, the University of Oxford, and University College Dublin.

They analysed lung tissue from patients with IPF and 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), both in cells cultured in the laboratory as well as in lung tissue from patients. 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 explained, "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."