Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation.
Ananda S MirchandaniStephen J JenkinsCalum C BainManuel A Sanchez-GarciaHannah LawsonPatricia CoelhoFiona MurphyDavid M GriffithAiliang ZhangTyler MorrisonTony LySimone ArientiPranvera SadikuEmily R WattsRebecca S DickinsonLeila ReyesGeorge CooperSarah ClarkDavid LewisVan KellyChristos SpanosKathryn M MusgraveLiam DelaneyIsla HarperJonathan ScottNicholas J ParkinsonAnthony J RostronJohn Kenneth BaillieSara Clohisey HendryClare PridansLara CampanaPhilip Starkey LewisA John SimpsonDavid H DockrellJürgen SchwarzeNikhil HiraniPeter J RatcliffeChristopher W PughKamil KrancStuart John ForbesMoira K B WhyteSarah R WalmsleyPublished in: Nature immunology (2022)
Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.
Keyphrases
- acute respiratory distress syndrome
- mechanical ventilation
- extracorporeal membrane oxygenation
- dendritic cells
- endothelial cells
- respiratory failure
- bone marrow
- end stage renal disease
- immune response
- oxidative stress
- chronic kidney disease
- ejection fraction
- newly diagnosed
- mesenchymal stem cells
- mouse model
- peritoneal dialysis
- pulmonary hypertension
- machine learning
- lipopolysaccharide induced
- physical activity
- intensive care unit
- lps induced
- type diabetes
- skeletal muscle
- inflammatory response
- metabolic syndrome
- high fat diet induced