Completed Lungs & Breathing Infection & Immunity

The role of leukotriene A4 hydrolase in dictating inflammation and remodelling in chronic lung diseases

Funder Wellcome Charity-funded
Recipient organisation Imperial College London
Funding £1.8M
Period May 2018 — May 2023

In plain English

AI plain-English summary

An enzyme called leukotriene A4 hydrolase (LTA4H) performs two opposing jobs—one that stokes inflammation and one that dampens it—and this project will determine how that balance goes wrong in chronic lung diseases. In healthy lungs, LTA4H both produces a molecule that recruits immune cells and breaks down a different molecule that also attracts immune cells. When this dual system is perturbed—by genetics, environmental insults, or both—the result can be persistent inflammation and pathological tissue remodelling. Current treatments for chronic lung diseases such as COPD, asthma, and pulmonary fibrosis do not address this underlying enzymatic imbalance, and patients are often treated without knowing which inflammatory pathway is driving their disease. If the research succeeds, it could enable clinicians to “endotype” patients—identifying which specific LTA4H-driven inflammatory or remodelling phenotype they have—and then match them to targeted therapies. The project will also test whether novel LTA4H modulators can restore the enzyme’s normal dual function, potentially offering a new class of drugs for chronic lung diseases that affect millions of people worldwide.

View original technical description
Whilst inflammation and ensuing repair are critical to the body’s response to infection/injury, aberrant inflammatory and reparative processes and subsequent pathological remodelling are cardinal features of chronic lung diseases (CLDs). I believe the enzyme leukotriene A4 hydrolase (LTA4H) critically regulates inflammation/repair processes through dual activities that generate lipid mediator leukotriene B4 (LTB4) but degrade matrikine Pro-Gly-Pro (PGP). PGP is a neutrophil chemoattractant whilst LTB4 drives the recruitment/activation of numerous immune cells. Additionally, I now demonstrate that PGP regulates epithelial and fibroblast functions critical to repair/remodelling. I hypothesise that intrinsic and extrinsic perturbation of the LTA4H axis drives distinct pathological inflammatory and remodelling phenotypes in CLDs. The key goals of this proposal are: 1. Dissect how the dual functions of LTA4H regulate pathological inflammatory and remodelling features of CLDs, and infer if novel LTA4H modulators show therapeutic potential. 2. Understand how LTA4H is perturbed by genetic influences and environmental insults resulting persistent inflammation and pathological remodelling. 3. Evaluate the LTA4H axis in CLD patients to ascertain why it is aberrant and how it correlates with pathological and clinical endpoints. These studies examine biological pathways that define the balance between health and disease, and will facilitate the endotyping of patients for therapeutic intervention.

View the original record at the funder ↗

Researchers

Robert Snelgrove (EPMC Awardee)

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Original classification

Senior Research Fellowship Basic

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