Barrier breakdown: lung-brain crosstalk in systemic inflammation

The lung and brain engage in a dynamic, bidirectional communication that influences immune homeostasis both locally and systemically, shaping overall health and disease progression. Lung infection is increasingly recognized for its role in triggering or exacerbating neurological dysfunction, ultimately worsening clinical outcomes. Although the brain is shielded by the blood-brain barrier (BBB), it remains vulnerable to secondary injury during pulmonary infection, primarily through lung-driven systemic inflammation, immune cell activation, and the release of cytokines, chemokines, and other circulating mediators. This review explores the biological and immunological mechanisms underlying lung-to-brain communication, with a focus on cerebral alterations following pulmonary bacterial infection. We examine the contributions of circulating mediators such as degradation products of the endothelial glycocalyx (eGC), endothelial proteins, inflammatory cytokines, and others originating from the lung and impacting the central nervous system (CNS). We highlight emerging insights into how lung-triggered systemic inflammation causes neurological sequelae, including cognitive deficits and behavioral changes. Finally, we discuss recent experimental findings and clinical evidence that advance our understanding of the detrimental interplay between pulmonary inflammation and brain dysfunction. We then outline the clinical relevance, therapeutic translation and opportunities for future research. The mediators discussed here point to emerging therapeutic targets and highlight the clinical challenges of preventing long-term neurological complications of bacterial lung infections.