Pulmonary fibrosis: ion channel regulates tissue remodeling

An international research team led by LMU has identified a previously unknown mechanism which can contribute to the development of pulmonary fibrosis. At the heart of their investigation is the lysosomal ion channel TRPML1. If this channel is absent, an important cellular process gets out of balance: The controlled release of certain enzymes is disrupted. These enzymes are normally responsible for breaking down structural proteins like collagen and elastin, thus preserving the stability and functionality of the tissue.

If this breakdown is lacking, collagen and elastin build up in lung tissue. This results in structural and functional changes which strongly correspond to the clinical picture of pulmonary fibrosis. In this way, the study opens up a novel molecular approach to antifibrotic therapies, for which there is much demand. The findings of the study were published in The EMBO Journal.

When the lungs become scarred

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Background: Pulmonary fibrosis is a severe, currently incurable disease. The lung tissue thickens and scars, its elasticity decreases, and oxygen absorption gets progressively worse. A characteristic feature is the excessive deposition of extracellular matrix, particularly collagen and elastin. These structural proteins are usually broken down by matrix metalloproteinases (MMPs) in a controlled manner. If this balance gets out of kilter, the tissue can increasingly harden.

The team lead by Professor Christian Michael Grimm from the Walther Straub Institute of Pharmacology and Toxicology at LMU investigated transgenic mice without the TRPML1 ion channel. This channel is located in lysosomes – that is, in the organelles of cells. Lysosomes are involved, among other things, in recycling and the controlled release of enzymes.

“We were able to show for the first time that TRPML1 controls the release of multiple antifibrotic matrix metalloproteinases,” says Grimm. “If this channel is absent, the enzymes do not reach the extracellular space in sufficient quantities – the tissue hardens.”

Fibrosis-like phenotype with measurable functional losses

The functional effects of the missing channel were clear: The lungs of the knockout mice exhibited increased stiffness and reduced elasticity, while histological staining revealed increased deposition of collagen and elastin in the pulmonary tissue.

Notably, the observed phenotype corresponds in many parameters with the established bleomycin model of pulmonary fibrosis, where administration of the cytostatic drug bleomycin leads to inflammation-triggered fibrotic scar formation in the lung. Additional bleomycin treatment did not further deteriorate the condition of TRPML1-deficient animals in the current experiment. Clearly, the fibrotic process had already developed to its maximum extent.

“Functionally and histologically, the changes we observe are scarcely any different from the classical experimental fibrosis model,” says Grimm. “This underscores the key role of TRPML1 in the tissue remodeling of the lung.”

Outlook: a novel therapeutic approach?

In experiments, the team demonstrated that the targeted pharmacological activation of TRPML1 significantly increases the release of the affected matrix metalloproteinases, importantly only in cells with an intact channel and not in cells lacking the channel.

In addition, the researchers can point to another important discovery: Mutations in the TRPML1 gene cause the rare lysosomal storage disorder mucolipidosis type IV (MLIV). The current results suggest that patients might carry a formerly underestimated risk of fibrotic changes in the lung. “Our findings thus not only open up new prospects for the treatment of pulmonary fibrosis, but also cast a new light on systemic effects of lysosomal diseases,” says Grimm.

Eva-Maria Weiden et al. TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition. The EMBO Journal 2026