CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in murine model of the SARS-CoV-2-related acute respiratory distress syndrome
bioRxiv (Cold Spring Harbor Laboratory)(2023)
摘要
The acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis is one of the main causes of high mortality in patients with COVID-19 (novel coronavirus disease 2019) – ongoing SARS-CoV-2 infection, reached more than 0.7 billion registered cases. Recently we elaborated non-surgical and reproducible method of unilateral total diffuse alveolar damage (DAD) of the left lung in ICR mice – a publicly available imitation of the ARDS caused by SARS-CoV-2. Our data reads that two C-C chemokine receptor 5 (CCR5) ligands – macrophage inflammatory proteins (MIP) – (MIP-1a/CCL3) and (MIP-1b/CCL4) are upregulated in this DAD model up to three orders of magnitude compared to the background level. Here we showed that a nonpeptide compound TAK-779, antagonist of CCR5/CXCR3, readily prevents DAD of the lung with a single injection of 2.5 mg/kg. Histological analysis revealed reduced peribronchial and perivascular mononuclear infiltration in the lung, and mononuclear infiltration of the wall and lumen of the alveoli in the TAK-779-treated animals. Administration of the TAK-779 decreased 3-5-fold level of serum cytokines and chemokines in animals with DAD, including CCR5 ligands MIP-1a/b, MCP-1 and CCL5. Computed tomography revealed rapid recovery of the density and volume of the affected lung in TAK-779-treated animals. Our pre-clinical data suggest that TAK-779 is more effective than administration of dexamethasone or anti-IL6R therapeutic antibody tocilizumab, which brings novel therapeutic modality to TAK-779 and other CCR5 inhibitors recruited in ongoing clinical studies as a potential drugs for treatment of COVID19 and similar virus-induced inflammation syndromes.
### Competing Interest Statement
The authors have declared no competing interest.
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