{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:26:48Z","timestamp":1787030808788,"version":"build-2736575974"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Acute brain injury (ABI) frequently precipitates severe extracranial target-organ complications, with the lungs being the most directly and fatally affected distant organs. Traditionally, the rapid onset of pulmonary dysfunction following brain injury has been attributed to the \u201cmassive catecholamine release\u201d\u2014a massive, dysregulated release of catecholamines leading to intense systemic vasoconstriction, elevated pulmonary capillary hydrostatic pressure, and subsequent neurogenic pulmonary edema. However, this purely neuro-hemodynamic model falls short of explaining the delayed onset and highly inflammatory nature of acute respiratory distress syndrome that persists during the later stages of injury. Recently, the discovery of the glymphatic system has provided a groundbreaking molecular and anatomical framework for understanding the pathological crosstalk within the \u201cbrain-lung axis.\u201d As a macroscopic waste clearance network within the central nervous system highly dependent on the polarized expression of aquaporin-4 (AQP4), the glymphatic system undergoes structural and functional severe impairment following ABI. The loss of AQP4 polarization, coupled with reactive astrogliosis, halts cerebrospinal fluid-interstitial fluid exchange. This drainage failure not only forces the massive accumulation of damage-associated molecular patterns and pro-inflammatory cytokines within the brain parenchyma but also drives the systemic \u201cspillover\u201d of high-concentration neurogenic toxins through enzymatic disruption of the blood\u2013brain barrier and the hijacked meningeal lymphatics. These brain-derived mediators\u2014whether circulating freely or encapsulated within extracellular vesicles\u2014travel via the systemic circulation to the pulmonary capillary bed. Upon reaching the lungs, they specifically target pulmonary microvascular endothelial cells by binding to TLR4 and RAGE receptors, triggering the phosphorylation and internalization of vascular endothelial cadherin, and thus completely dismantling the endothelial barrier. Concurrently, these signals drive the M1 polarization of alveolar macrophages, eliciting destructive neutrophil infiltration and parenchymal damage. Crucially, this pulmonary dysfunction generates severe hypoxemia and releases lung-derived inflammatory mediators that feed back to the central nervous system, establishing a fatal bidirectional vicious cycle. This narrative conceptual review aims to comprehensively dissect the bidirectional immune-inflammatory cascade network of the brain-lung axis triggered by glymphatic collapse and systematically evaluate the latest therapeutic prospects, considering the impact of pre-morbid systemic stressors and mechanical ventilation, while targeting AQP4 modulation, lymphangiogenesis, and systemic inflammation blockade.<\/jats:p>","DOI":"10.3389\/fneur.2026.1844527","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:29:16Z","timestamp":1787027356000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Network mechanisms of glymphatic system dysfunction in the disruption of the \u201cbrain-lung axis\u201d"],"prefix":"10.3389","volume":"17","author":[{"given":"Lielong","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The Second Hospital of Zhuzhou","place":["Zhuzhou, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Affairs, The Second Hospital of Zhuzhou","place":["Zhuzhou, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feijun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Scientific Research, The Second Hospital of Zhuzhou","place":["Zhuzhou, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.5492\/wjccm.v4.i3.163","article-title":"Brain-lung crosstalk: implications for neurocritical care patients","volume":"4","author":"Mrozek","year":"2015","journal-title":"World J Crit Care 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