Abstract
IntroductionAcute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life‐threatening hypoxaemia. Although ARDS can be caused by a variety of pathogens or major trauma, it is best known as the major cause of mortality in COVID‐19 patients. Since ARDS is often associated with dysregulated inflammatory immune responses, immunomodulatory approaches represent a possible treatment option. The objective of this study was to evaluate the therapeutic potential of interleukin (IL)‐1 blockade using Anakinra in a mouse model of lipopolysaccharide (LPS)‐induced ALI.MethodsWe evaluated the effects of a daily subcutaneous Anakinra treatment in a mouse model of LPS‐induced ALI. We monitored body weight to assess the general health status of the mice. Two days after ALI induction, we evaluated the inflammatory cytokine MIP‐2 as well as protein levels in bronchoalveolar lavage (BAL) fluids. Two and nine days after ALI induction, we evaluated infiltrating leukocytes in BAL fluid and lung tissue.ResultsAnakinra treatment reduced ALI‐induced weight loss compared to nontreated groups. At Day 2, Anakinra treatment reduced levels of MIP‐2 and protein in BAL fluids and reduced frequencies of NK cells and neutrophils in the lung tissue. Nine days after ALI induction, Anakinra treated mice displayed reduced levels of neutrophils and alveolar macrophages in BAL fluids.ConclusionsIL‐1 blockade using Anakinra reduced classical hallmarks of inflammation in a mouse model of ALI. Our data support ongoing and future research on the evaluation of Anakinra as a potential treatment option in ARDS.
Highlights
Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life‐threatening hypoxaemia
A recent study showed that Anakinra (Kineret®), a recombinant version of the IL‐1 receptor antagonist IL‐1Ra, is beneficial in patients with severe forms of COVID‐19.9 Additional studies have come out since and shown positive trends regarding efficacy and safety of Anakinra in COVID‐19.10,11 Here, we show that Anakinra improves an experimental mouse model of ALI that is commonly used to study ARDS12 by reducing (i) lung inflammation, (ii) lung permeability for proteins, and (iii) neutrophil, NK cell and alveolar macrophages influx into the alveoli.[12,13]
In our model of LPS‐induced ALI, the observed cellular kinetics, with an early recruitment of neutrophils and a later recruitment of macrophages as well as higher levels of pulmonary MIP‐2 and protein levels is consistent with previous studies.[2,12,13]
Summary
Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life‐threatening hypoxaemia. “Hyper” and “hypo‐inflammatory” phenotypes of ARDS have been distinguished on the basis of expression levels of circulating proinflammatory cytokines and chemokines,[4] among which interleukin (IL)‐1 that has been shown to be involved in the immunopathology of acute lung injury (ALI).[5,6,7] In COVID‐19, the exact phenotype is still a matter of debate, but proinflammatory cytokines were shown to be dysregulated.[3,8] A recent study showed that Anakinra (Kineret®), a recombinant version of the IL‐1 receptor antagonist IL‐1Ra, is beneficial in patients with severe forms of COVID‐19.9 Additional studies have come out since and shown positive trends regarding efficacy and safety of Anakinra in COVID‐19.10,11 Here, we show that Anakinra improves an experimental mouse model of ALI that is commonly used to study ARDS12 by reducing (i) lung inflammation, (ii) lung permeability for proteins, and (iii) neutrophil, NK cell and alveolar macrophages influx into the alveoli.[12,13] These findings support research in the optimisation of Anakinra‐based therapy in the acute phase of ARDS with dysregulated inflammation
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