Work

Lysosomal pH dysregulation as a candidate signal-amplifying hub in sepsis-associated lung injury

Year: 2026

Type: review

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.

Source: Frontiers in Cellular and Infection Microbiology

DOI: 10.3389/fcimb.2026.1953667