Chronic obstructive pulmonary disease (COPD) refers to a group of diseases that cause airflow blockage and breathing-related problems. COPD affects 16 million Americans, 300 million people worldwide, and is the third most common cause of death in the world. A new mouse study by Ludwig-Maximilians-Universität München (LMU) pharmacologist Christian Grimm, PhD, from the Walther Straub Institute of Pharmacology and Toxicology, who collaborated with Martin Biel, PhD, professor, and Ali Önder Yildirim, PhD, demonstrates that specific ion channels in immune cells play a determining role in the inflammation process.

The findings are published in the journal Nature Communications in a paper titled, “Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice.”

“Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease,” the researchers wrote. “Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3−/− mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment.”

The researchers investigated the expression and function of TRPML3 in the lung in order to clarify how the MMP12 concentration is regulated. “To our surprise, we found that it is not the secretion of MMP12 that is impaired in COPD, but the endocytosis. As such, it is not that the inflammation causes more MMP12 to be released, but that the reabsorption of excess MMP12 by TRPML3 does not work well enough,” explained Grimm. “This is further supported by our demonstrating, with the aid of endolysosomal patch clamp technology, that the channel is expressed above all in the so-called early endosomes, whose job it is to absorb particles.”

“In sum, we show here that Trpml3−/− mice are highly vulnerable to emphysema and COPD development,” noted the researchers. “We further deliver a molecular rationale for the observed lung phenotype in Trpml3−/− mice, we introduce TRPML3 as a regulator of MMP-12 levels in BALF, we provide a possible mechanism for cell entry of MMP-12, and we propose TRPML3 as a potential drug target for COPD and emphysema treatment.”

Their findings suggest TRPML3 is a critical regulator of MMP-12 absorption through alveolar macrophages and could serve as a therapeutic target for COPD. Their findings will pave a way for new research and strategies that target these ion channels.

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