Pulmonary edema, a major complication of lung injury and inflammation, is defined as accumulation of extravascular fluid in the lungs leading to impaired diffusion of respiratory gases. Lung fluid balance across the alveolar epithelial barrier protects the distal airspace from excess fluid accumulation and is mainly regulated by active sodium transport and Cl− absorption. Increased hydrostatic pressure as seen in cardiogenic edema or increased vascular permeability as present in inflammatory lung diseases such as the acute respiratory distress syndrome (ARDS) causes a reversal of transepithelial fluid transport resulting in the formation of pulmonary edema. The basolateral expressed Na+-K+-2Cl− cotransporter 1 (NKCC1) and the apical Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR) are considered to be critically involved in the pathogenesis of pulmonary edema and have also been implicated in the inflammatory response in ARDS. Expression and function of both NKCC1 and CFTR can be modulated by released cytokines; however, the relevance of this modulation in the context of ARDS and pulmonary edema is so far unclear. Here, we review the existing literature on the regulation of NKCC1 and CFTR by cytokines, and—based on the known involvement of NKCC1 and CFTR in lung edema and inflammation—speculate on the role of cytokine-dependent NKCC1/CFTR regulation for the pathogenesis and potential treatment of pulmonary inflammation and edema formation.
Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5-15%. We previously showed that stored (5 days; D5) but not fresh platelets (1 day; D1) cause TRALI via ceramide mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induce TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. D5-EVs were more abundant, had higher long chain ceramide (C16:0, C18:0, C20:0) and lower S1P content than D1-EVs. Transfusion of D5- but not D1-EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet D4-EVs were more numerous compared with D2-EVs, contained more long chain ceramide and less S1P, and caused more EC barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention.
Approximately 20% of symptomatic patients with SARS-CoV-2 infection progress to severe coronavirus disease (COVID-19) with critical hypoxemia fulfilling the criteria of acute respiratory distress syndrome (ARDS). Consistent with the classic features of ARDS, severe COVID-19 is characterised by ground glass opacities in CT imaging and diffuse alveolar damage
post mortem
[5] suggesting permeability-type lung edema as driver of respiratory failure. Consistent with this concept, autopsy findings show severe lung endothelial injury in patients who succumbed to COVID-19 [1].
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.