Michael Croft, PhD, a researcher at the La Jolla Institute for Allergy and Immunology, has discovered the role a certain molecule plays as a major trigger for airway remodeling, which impairs lung function. The discovery makes the molecule a promising therapeutic target for chronic asthma, chronic obstructive pulmonary disease (COPD), and several other lung conditions. Croft’s findings have been published in the journal Nature Medicine.

The finding marks Croft’s second major discovery with therapeutic potential for asthma. He previously discovered a novel molecular mechanism driving lung inflammation, which is the basis for a potential asthma treatment now in Phase 2 human clinical trials.

Croft’s current research shows that blocking the interactions of LIGHT—the tumor necrosis factor (TNF) family of molecules discovered in 1998 and proven to be important players in inflammation-driven autoimmune diseases—with its two receptors significantly inhibited the process of airway remodeling in mouse models of chronic asthma.

Airway remodeling refers to inflammation-fueled structural changes in the lungs, including fibrosis, which can occur over time and result in declining lung function that strongly contributes to conditions such as COPD, chronic asthma, and several other respiratory disorders. Current therapies for asthma and COPD primarily include corticosteroids, bronchodilators, and leukotriene antagonists, but these are thought to have little impact, if any, on airway remodeling, according to Croft.

The emerging data on the role of the TNF super family of molecules in fueling inflammatory diseases, including Croft’s own finding on OX40 Ligand and its receptor’s action in triggering inflammation in asthma, prompted Croft to take a close look at LIGHT, a fellow TNF molecule.

“We hypothesized that LIGHT might be involved in driving aspects of lung inflammation or have a role in lung dysfunction that was different than our previous findings on OX40L,” said Croft. “As we were undertaking our studies, a report found that increased sputum LIGHT levels in people with asthma correlated with decreased lung function, which was in line with our thinking.”

In a related finding, published in the Journal of Experimental Medicine, Croft also showed a connection between LIGHT and T cell-fueled inflammation that contributes to other aspects of asthmatic disease.

“We showed that blocking LIGHT binding to one of its receptors, named the herpesvirus entry mediator, reduced the ability of T lymphocytes, induced with a model allergen, to survive long-term. This strongly curtailed lung inflammation associated with asthma when the allergen was subsequently inhaled,” said Croft.

Source: La Jolla Institute for Allergy and Immunology