Lysosomal pH dysregulation as a candidate signal-amplifying hub in sepsis-associated lung injury
5 affiliations
- 1Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University , ,
- 2Department of Emergency Medicine, The First Affiliated Hospital of Dalian Medical University , ,
- 3Department of Critical Care Medicine, The First Affiliated Hospital of Shihezi University , ,
- 4The First Clinical Medical College, Gannan Medical University , ,
- 5Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University , ,
Abstract
Sepsis-associated lung injury arises from a dysregulated host response to infection, but the organelle-level mechanisms linking microbial sensing to alveolar–capillary barrier failure remain incompletely resolved. This Review proposes lysosomal pH dysregulation as a candidate, context-dependent signal-amplifying hub rather than a universal initiating event. We synthesize evidence involving V-ATPase-dependent acidification, ClC-7/OSTM1-mediated chloride homeostasis, TMEM175-dependent ion conductance, mTORC1–TFEB signaling, mitochondrial stress, mitochondria–lysosome contact-site proton transfer, and autophagy–lysosome function while distinguishing direct organelle pH measurements from non-equivalent readouts such as membrane permeabilization, cathepsin redistribution, LysoTracker intensity, and autophagic flux. Of 21 formally appraised mechanistic axes, only 2 met Level I criteria; most evidence was Level III or IV and therefore extrapolative or hypothesis-generating. Across macrophages, epithelial cells, pulmonary endothelial cells, and fibroblasts, lysosomal dysfunction may impair pathogen clearance and cellular quality control while amplifying inflammatory signaling and alveolar–capillary barrier injury. We therefore position lysosomal pH homeostasis as a testable mechanistic and stratification axis whose relevance is likely to vary by compartment, cell type, and disease stage.
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BibTeX
@article{tu2026lysosomal,
title = {{Lysosomal pH dysregulation as a candidate signal-amplifying hub in sepsis-associated lung injury}},
author = {Gengjia Tu and Zhijie Deng and Yuling Li and Peigang Tian and Yu Shen and Yanyan Deng and Zhiyuan Zhang and Yi Liu and Shouwei Zhong and Jianjun Wu and Hongquan Zhu and Jiamin Ma and Jianhua Li},
journal = {Frontiers in cellular and infection microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1953667},
url = {https://europepmc.org/article/PMC/PMC13728857},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lysosomal pH dysregulation as a candidate signal-amplifying hub in sepsis-associated lung injury
AU - Gengjia Tu
AU - Zhijie Deng
AU - Yuling Li
AU - Peigang Tian
AU - Yu Shen
AU - Yanyan Deng
AU - Zhiyuan Zhang
AU - Yi Liu
AU - Shouwei Zhong
AU - Jianjun Wu
AU - Hongquan Zhu
AU - Jiamin Ma
AU - Jianhua Li
PY - 2026
DA - 2026/10/20
JO - Frontiers in cellular and infection microbiology
DO - 10.3389/fcimb.2026.1953667
UR - https://europepmc.org/article/PMC/PMC13728857
AB - Sepsis-associated lung injury arises from a dysregulated host response to infection, but the organelle-level mechanisms linking microbial sensing to alveolar–capillary barrier failure remain incompletely resolved. This Review proposes lysosomal pH dysregulation as a candidate, context-dependent signal-amplifying hub rather than a universal initiating event. We synthesize evidence involving V-ATPase-dependent acidification, ClC-7/OSTM1-mediated chloride homeostasis, TMEM175-dependent ion conductance, mTORC1–TFEB signaling, mitochondrial stress, mitochondria–lysosome contact-site proton transfer, and autophagy–lysosome function while distinguishing direct organelle pH measurements from non-equivalent readouts such as membrane permeabilization, cathepsin redistribution, LysoTracker intensity, and autophagic flux. Of 21 formally appraised mechanistic axes, only 2 met Level I criteria; most evidence was Level III or IV and therefore extrapolative or hypothesis-generating. Across macrophages, epithelial cells, pulmonary endothelial cells, and fibroblasts, lysosomal dysfunction may impair pathogen clearance and cellular quality control while amplifying inflammatory signaling and alveolar–capillary barrier injury. We therefore position lysosomal pH homeostasis as a testable mechanistic and stratification axis whose relevance is likely to vary by compartment, cell type, and disease stage.
SN - 2235-2988
ER -