Denise Battaglini, Giulia Bonatti, Chiara Robba, Patricia RM Rocco, Paolo Pelosi
We would like to thank Zhang and collaborators for reading with interest our recent review  concerning the role of mechanical ventilation in patients with acute ischemic stroke. The authors highlighted the role of acute ischemic stroke on pulmonary complications and their association with clinical outcome and death. Indeed, the mechanisms associated with pulmonary complications after acute ischemic stroke are complex and further studies are required. In Fig. 1, we highlighted the main mechanisms of acute ischemic stroke-induced lung inflammation.
After vessel occlusion, oxygen and glucose deprivation induces neuronal and glial cell death, followed by the release of damage-associated molecular patterns (DAMPs) that include adenosine triphosphate (ATP), glutamate, and reactive oxygen species (ROS). These molecules bind to toll-like receptors (TLRs)-2, TLR-4, and receptor for advanced glycation end products (RAGE), activating resident microglial cells and stimulating the release of pro-inflammatory cytokines (such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6). Glutamate binds N-methyl-d-aspartate receptors (NMDA) increasing calcium influx and producing ROS .
Sympathetic nervous system, efferent vagus nerve, and hypothalamic-pituitary-adrenal (HPA) axis are overactivated by acute ischemic stroke and may induce immunosuppression. Particularly, the efferent vagus acts through the release of acetylcholine (Ach) that binds nicotinic acetylcholine receptor (nAchRα7) both on lung alveolar macrophages and epithelial cells reducing inflammation and neuronal cells protecting against oxidative stress . Catecholamines (on β2, α2, and D2 receptors) are released by sympathetic nervous system and activate T regulator lymphocytes with the liberation of interferon (IFN)-γ and IL-10. Moreover, HPA axis induces glucocorticoid secretion, thus activating apoptosis of lymphocytes, releasing IL-10, and reducing IFN-γ liberation by T cells .
Blood-brain barrier permeability is increased, and inflammatory cells are released into the systemic circulation. Microglia (M) are polarized into M1 (classically activated) or M2 (alternatively activated) phenotypes. Activation of these phenotypes affects the prognosis of stroke . The M2 phenotype plays a protective role in the brain by releasing transforming growth factor-β, whereas inflammatory cytokines induced by M1 phenotype aggravate brain injury after stroke .
Therefore, systemic inflammation is activated. Diffuse alveolar damage with lung edema and inflammation have been observed after acute ischemic stroke in mice associated with enhanced pro-inflammatory cytokines and reduced phagocytic capability of lung macrophages .
Although significant progress has been made in the pathogenesis of stroke and its interaction with peripheral organs, further investigations are needed to elucidate stroke-induced immunosuppression and its potential therapeutic strategies.