Brain–lung axis and neuroimmune crosstalk in acute brain injury

Acute brain injury (ABI) frequently coexists with pulmonary complications, creating bidirectional interactions that can amplify secondary organ injury. This review reframes ABI-associated brain–lung crosstalk as a sequential neuroimmune relay—from generation and peripheral egress of CNS-derived signals, through systemic immune amplification and pulmonary effector injury, to reciprocal lung-to-brain feedback—and explicitly distinguishes directly supported mechanisms from emerging hypotheses. Following ABI, autonomic activation, damage-associated molecular patterns, extracellular vesicles, and peripheral immune responses may contribute to pulmonary endothelial dysfunction, innate immune activation, and alveolar-capillary barrier injury. Glymphatic and lymphatic clearance pathways are discussed as potential routes of CNS-to-systemic molecular transport, but direct evidence linking glymphatic-derived signals to pulmonary injury remains lacking. Conversely, acute pulmonary complications relevant to neurocritical illness—including ALI/ARDS, mechanical ventilation-associated injury, and pulmonary infection—may aggravate the vulnerable brain through systemic inflammation, impaired gas exchange, blood–brain barrier dysfunction, and neuroinflammatory signaling. We further evaluate candidate circulating biomarkers according to their biological source, specificity, and clinical readiness, emphasizing that currently available markers primarily reflect neural injury, endothelial dysfunction, or systemic inflammation rather than brain–lung axis injury itself. Therapeutic strategies targeting inflammasome signaling, autonomic regulation, immune modulation, microbiome-related pathways, and extracellular vesicles are assessed according to their mechanistic evidence and translational stage. By integrating directionality, evidence strength, and translational maturity, this review provides an ABI-centered framework for identifying experimentally testable relay points and priorities for future brain–lung research.