CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome.

Introduction: 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. Methods: Recently, we elaborated a non-surgical and reproducible method of the 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 read that two C-C chemokine receptor 5 (CCR5) ligands, macrophage inflammatory proteins (MIPs) MIP-1α/CCL3 and MIP-1ß/CCL4, are upregulated in this DAD model up to three orders of magnitude compared to the background level. Results: Here, we showed that a nonpeptide compound TAK-779, an antagonist of CCR5/CXCR3, readily prevents DAD in 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 TAK-779 decreased the 3-5-fold level of serum cytokines and chemokines in animals with DAD, including CCR5 ligands MIP-1α/ß, MCP-1, and CCL5. Computed tomography revealed rapid recovery of the density and volume of the affected lung in TAK-779-treated animals. Discussion: Our pre-clinical data suggest that TAK-779 is more effective than the administration of dexamethasone or the anti-IL6R therapeutic antibody tocilizumab, which brings novel therapeutic modality to TAK-779 and other CCR5 inhibitors for the treatment of virus-induced hyperinflammation syndromes, including COVID-19.

Plasma Cytokines Level and Spinal Cord MRI Predict Clinical Outcome in a Rat Glial Scar Cryoinjury Model.

Traumatic injury of the spinal cord is still one of the most challenging problems in the neurosurgical practice. Despite a long history of implementation of translational medicine in the field of spinal cord injury (SCI), it remains one of the most frequent causes of human disability and a critical situation for world healthcare systems. Here, we used our rat model of the of unilateral controlled SCI induced by a cryoinjury, which consistently reproduces glial scarring and posttraumatic cyst formation, and specifically evaluated histological, bioimaging and cytokine data. We propose a 10-grade scoring scale, which can objectively estimate the extent of damage of the experimental SCI according to the magnetic resonance imaging (MRI) results. It provides a homogeneous and reliable visual control of the dynamics of the posttraumatic processes, which makes it possible to clearly distinguish the extent of early damage, the formation of glial scars and the development of posttraumatic syringomyelic cysts. The concentration of cytokines and chemokines in the plasma following the experimental SCI increased up to two orders of magnitude in comparison with intact animals, suggesting that a traumatic injury of the spinal cord was accompanied by a remarkable cytokine storm. Our data suggested that the levels of IL-1α, IL-1ß, TNFα, GRO/KC, G-CSF, IFNγ and IL-13 may be considered as a reliable prognostic index for SCI. Finally, we demonstrated that MRI together with plasma cytokines level directly correlated and reliably predicted the clinical outcome following SCI. The present study brings novel noninvasive and intravital methods for the evaluation of the therapeutic efficacy of SCI treatment protocols, which may be easily translated into the clinical practice.