Sepsis-associated acute lung injury: do inflammatory lipid mediators flood the lungs by activating pulmonary TRP channels?

Although prevalent in critical care, sepsis-associated acute lung injury (sALI) lacks a clear mechanistic framework and disease-modifying therapies. In this narrative review, we synthesize clinical and experimental data implicating lipid mediators (LMs) as underappreciated drivers of pulmonary barrier failure in sALI. LMs are known activators or sensitizers of transient receptor potential (TRP) channels expressed in non-neuronal lung cells. In endothelial and epithelial compartments, activation of TRP channels elevates intracellular Ca²⁺, increases microvascular permeability, impairs alveolar fluid clearance, and promotes pulmonary edema. Converging metabolomic and translational studies associate accumulation of specific LMs with respiratory failure, providing a mechanistic link between the LMs and TRP-dependent barrier dysfunction. We propose the activation of TRP channels by LMs as a key underlying mechanism of sALI. Clarifying this mechanism, biomarker-guided studies may enable more targeted clinical trials and ultimately improve outcomes in sALI.