Endolysosomal cation channels and toxic chronic lung disease

Spix, Barbara Julia (2022): Endolysosomal cation channels and toxic chronic lung disease. Dissertation, LMU München: Medizinische Fakultät

Abstract

Chronic obstructive pulmonary disease (COPD) is a prevalent disease that affects million people worldwide. Classified as the third most common cause of death globally, it accounts for more than 3 million deaths per year. Smoking constitutes the main risk factor for developing COPD, while other factors include inhalation of environmental pollutants such as exhaust fumes from the industry or vehicles, occupational dusts and fumes, or genetic predispositions. Characteristic for COPD is a chronically inflamed lung and permanent pathological changes of the airways and lung tissue. Consequently, this leads to common symptoms like chronic cough, sputum, and shortness of breath, all of which significantly affect the quality of life. Two common forms of COPD can be described: chronic bronchitis associated with mucus hyper-production, and emphysema resulting from destruction of alveolar tissue, e.g. due to an excess of the macrophage elastase MMP-12. However, treatment options are poor, as no drugs are currently available that can slow down COPD progression or reduce the disease mortality. Thus, it is important and necessary to uncover novel treatment strategies and drug tarets. In this dissertation, the endolysosomal cation channel TRPML3 was investigated in the context of COPD and emphysema development with the aim to evaluate its potential as therapeutic target. Being located on membranes of intracellular organelles such as early endosomes and lysosomes, TRPML3 is involved in membrane fusion and fission events including endocytosis, trafficking, exocytosis, and autophagy. Here, by the use of the following novel reporter mouse line, Trpml3-IRES-Cre/eR26-τGFP, TRPML3 was found to be mainly expressed in alveolar macrophages (AMΦ) in the lungs. Further studies on lung function, and examination of lung tissues revealed that Trpml3 deficient (Trpml3-/-) mice show a pulmonary emphysema phenotype. This was demonstrated under both basal conditions and toxic conditions, meaning the exposure to cigarette smoke to induce COPD, and the application of a porcine pancreatic elastase to induce emphysema in the lungs. Analysis of bronchoalveolar lavage fluid (BAL-F) obtained from Trpml3-/- mice unveiled increased levels of the AMΦ-specific protease MMP-12, whereas other inflammatory cytokines, proteases and antiproteases, i.e. tissue inhibitor of metalloproteinases (TIMPs), were unchanged. Furthermore, loss of TRPML3 in AMΦ did not affect lysosomal exocytosis, but resulted in impairments in endolysosomal trafficking and endocytosis, being causative for the increased levels of MMP-12 also found in AMΦ cell culture supernatants and likely in BAL-F. Overall, this work discovered a significant role of TRPML3 in COPD and emphysema development. Mice lacking TRPML3 were unveiled to be particularly susceptible for developing pulmonary emphysema, attributed to the reduced capacity of Trpml3-/- AMΦ to balance the MMP-12 concentration in the lungs properly (Figure 1). Functioning as such a key regulator for MMP-12, TRPML3 may be considered as novel therapeutic target structure for the treatment of COPD.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 29. April 2022
• 1. Bericht­erstatter:in: Grimm, Christian