Research Progress on Translational Mechanisms of Bidirectional Cascading Lung–Brain Injury Induced by Blast Shockwaves: Insights from the “Lung–Brain Axis”

Blast-shockwave injury constitutes a major cause of casualties in modern local wars, terrorist attacks, and industrial explosion accidents. Blast-exposed casualties frequently suffer combined pulmonary and cerebral injuries. Secondary brain injury can be triggered by thoracic blast exposure even without direct cranial impact, yet its underlying mechanisms remain incompletely elucidated. As a bidirectional homeostatic regulatory network between the lung and the central nervous system, the lung–brain axis mediates inter-organ pathological signal transmission via neural circuits, humoral circulation, immune cell trafficking, extracellular vesicles, and mitochondrial-oxidative stress pathways, and serves as the core mediator for bidirectional cascading lung–brain injuries following blast insult. In this narrative review, we summarize the anatomical and physiological basis of the lung–brain axis under blast-shockwave injury. We elaborate the dual pathological processes: a pulmonary-derived inflammatory storm amplifying brain damage, and brain-originated neuro-endocrine mediators reciprocally aggravating pulmonary injury. We further explicitly distinguish mechanisms experimentally validated in blast injury animal models versus putative mechanisms extrapolated from non-blast inflammatory or trauma settings. The mediating roles of immune cells, extracellular vesicles, mitochondrial-oxidative stress, and autonomic nervous system dysfunction in lung–brain signal crosstalk are also summarized. We highlight existing research limitations, including insufficient integrated analysis of pathway-to-pathway crosstalk, the lack of genetic rescue validation for several pathological mechanisms, the scarcity of large-sample clinical cohort evidence, inadequate systematic interpretation of differential lung–brain axis regulation under diverse blast exposure conditions, and limited in vivo evidence proving the complete self-perpetuating closed-loop bidirectional pathological cycle. Future research priorities are proposed from four perspectives: deciphering multi-pathway molecular regulatory networks, developing combinatorial biomarker panels specific for the lung–brain axis, establishing individualized therapeutic strategies with dual lung–brain protective effects, and advancing clinical translation and simulation studies. In-depth mechanistic exploration of the lung–brain axis in blast injury provides novel theoretical foundations for the early warning, biomarker screening, prevention, and clinical management of combined blast-induced lung–brain injuries.