ADAM17 inhibition prevents neutrophilia and lung injury in a mouse model of Covid-19
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Abstract
Severe coronavirus disease 2019 (Covid-19) is characterized by lung injury, cytokine storm and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe Covid-19 in infected individuals. Angiotensin-converting enzyme-2 ACE-2) is the receptor for SARS-CoV-2, the virus causing Covid-19, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE-2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates Covid-19-related lung inflammation. We employed a pre-clinical mouse model using intra-tracheal instillation of a combination of polyinosinic:polycytidylic acid (poly-I:C) and the receptor-binding domain of the SARS-CoV-2 spike protein (RBD-S) to mimic lung damage associated with Covid-19. Histological analysis of inflamed mice confirmed the expected signs of lung injury including edema, fibrosis, vascular congestion and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill Covid-19 patients. Administration of the ADAM17 inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of pro-inflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17 inhibition. Thus, we propose inhibition of ADAM17 as a novel promising treatment strategy in SARS-CoV-2-infected individuals to prevent the progression towards severe Covid-19.
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SciScore for 10.1101/2021.04.10.439288: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: All protocols have been approved by the institutional animal care and use committee of CINVESTAV Randomization not detected. Blinding A pathologist analyzed the samples for the degree of inflammation in a blinded fashion and determined the histopathological scores as previously published (22). Power Analysis not detected. Sex as a biological variable Experimental Animals: Pathogen-free 8-12 weeks old C57BL/6 male mice were obtained from the animal facility in CINVESTAV. Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources Experimental Animals: Pathogen-free 8-12 weeks old C57BL/6 male mice were obtained from the animal facility in CINVESTAV. C57…SciScore for 10.1101/2021.04.10.439288: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: All protocols have been approved by the institutional animal care and use committee of CINVESTAV Randomization not detected. Blinding A pathologist analyzed the samples for the degree of inflammation in a blinded fashion and determined the histopathological scores as previously published (22). Power Analysis not detected. Sex as a biological variable Experimental Animals: Pathogen-free 8-12 weeks old C57BL/6 male mice were obtained from the animal facility in CINVESTAV. Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources Experimental Animals: Pathogen-free 8-12 weeks old C57BL/6 male mice were obtained from the animal facility in CINVESTAV. C57BL/6suggested: NoneSoftware and Algorithms Sentences Resources Data were acquired using a FASC Canto II and analyzed using FlowJo V10 software. FlowJosuggested: (FlowJo, RRID:SCR_008520)Statistical Analysis: Data were analyzed using GraphPad Prism Version 6.0. GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 34. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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