A new mouse unilateral model of diffuse alveolar damage of the lung

Chernov, Aleksandr S.; Minakov, A. A.; Казаков, В. А.; Родионов, Максим; Rybalkin, I. N.; Власик, Т. Н.; Yashin, Denis V.; Saschenko, L. P.; Kudriaeva, Anna; Belogurov, A. A.; Смирнов, Иван; Loginova, S. Ya.; Schukina, V. N.; Savenko, S. V.; Борисевич, С. В.; Zykov, K. A.; Gabibov, Alexander; Telegin, G. B.

doi:10.1007/s00011-022-01568-0

Cited by 9 publications

(6 citation statements)

References 48 publications

(41 reference statements)

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“…In our previous study [15], we successfully demonstrated that E. coli-induced acute lung injury using ICR mouse showed significant increases in lung injury, including alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickness, as well as inflammatory cytokine levels, which are similar to those observed in clinical ALI/ARDS [18]. The ICR mouse strain is commonly used in in vivo disease models, including acute lung injury, as reported in other previous studies [19,20]. Furthermore, it is known that C57BL/6 mice and ICR mice have similar physiological features and metabolic phenotypes [21].…”

Section: Discussionsupporting

confidence: 58%

SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury

Kim

Sung

Bang

et al. 2023

IJMS

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Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.

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Section: Discussionsupporting

confidence: 58%

SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury

Kim

Sung

Bang

et al. 2023

IJMS

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“…Five animals from each group were sacrificed at day 7 and 45 and histological studies were performed, as described previously [55,92]. Briefly, the lungs were filled with 10% solution of neutral formalin, embedded in paraffin and 4–5 μm width sections were stained with hematoxylin and eosin.…”

Section: Methodsmentioning

confidence: 99%

“…These features limit statistical analysis and yield binary “yes or no” result of the experimental therapy. Here we assessed therapeutic effect of dexamethasone, tocilizumab and TAK- 779 on the course of the ARDS in non-lethal, highly reproducible ICR DAD murine model mimicking SARS-CoV-2 infection [55] using histological evaluation, cytokine profiling and computed tomography analysis.…”

Section: Introductionmentioning

confidence: 99%

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

Chernov,

Rodionov,

Kazakov

et al. 2023

Preprint

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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-1α/CCL3) and (MIP-1β/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-1α/β, 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.Abstract summaryThe pathogenesis of the SARS-CoV-2 infection is tightly linked with the cytokine storm resulting in the enormous release of cytokines and chemokines. Its clinical manifestation – the acute respiratory distress syndrome (ARDS), may be caused by self-sustaining hypersensitivity reactions leading to lung collapse even after virus clearance. Here we report that two macrophage inflammatory proteins, MIP-1α/CCL3 and MIP-1β/CCL4, seem to orchestrate mononuclear infiltration into the lungs during diffuse alveolar damage (DAD) in ICR mice – our murine model of ARDS caused by SARS-CoV-2. Inhibition of the C-C chemokine receptor 5 (CCR5) – parental receptor for MIP-1α and MIP-1β, by nonpeptide antagonist TAK-779 results in significant amelioration of DAD in terms of reduced mononuclear infiltration into the lung, suppressed cytokine storm and restored physiology of affected lung according to computed tomography data. We suggest that targeted inhibition of CCR5 should be further elucidated as safe and effective approach to overcome severe viral pneumonia in humans.

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“…Infection of mice with the SARS-CoV-2 virus. Thirty-six days after the first immunization, all C57BL/6-TgTn(CAG-humanACE2-IRES-Luciferase-WPRE-polyA) mice were transferred to a specialized ABSL-3 level laboratory (Sergiev Posad), where they were infected with the Wuhan SARS-CoV-2 strain by intranasal administration of the SARS-CoV-2 virus at a dose of 3 log PFU in a volume of 20 μL of saline [38]. In mice that died during the observation period, the cardiopulmonary complex was extirpated and, after two weeks of inactivation in 10% formalin solution, was sent for histological examination.…”

Section: Assessment Of the Protective Efficacy Of Formulation L 1 In ...mentioning

confidence: 99%

Proof-of-Concept Study of Liposomes with a Set of SARS-CoV-2 Viral Peptidic T-Cell Epitopes as a Vaccine

et al. 2022

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Potential nonameric epitopes of CD8 + T lymphocytes were selected from the composition of structural, accessory, and nonstructural proteins of the SARS-CoV-2 virus (13 peptides) and a 15-mer epitope of CD4 + T lymphocytes, from the S-protein, based on the analysis of publications on genome-wide immunoinformatic analysis of T-cell epitopes of the virus (Wuhan strain), as well as a number of clinical studies of immunodominant epitopes among patients recovering from COVID-19 disease. The peptides were synthesized and five compositions of 6–7 peptides were included in liposomes from egg phosphatidylcholine and cholesterol (~200 nm size) obtained by extrusion. After double subcutaneous immunization of conventional mice, activation of cellular immunity was assessed by the level of cytokine synthesis by splenocytes in vitro in response to stimulation with relevant peptide compositions. Liposomal formulation exhibiting the best result in terms of the formation of specific cellular immunity in response to vaccination was selected for further experiments. Evaluation of the protective efficacy of this formulation in an infectious mouse model showed a positive trend in the frequency of occurrence of hyaline-like membranes in the lumen of the alveoli, as well as a somewhat lower severity of microcirculatory disorders. The latter circumstance can potentially help reduce the severity of the disease and prevent its adverse outcomes. A method to produce liposome preparations with peptide compositions for long-term storage is under development.

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A new mouse unilateral model of diffuse alveolar damage of the lung

Cited by 9 publications

References 48 publications

SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury

SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury

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

Proof-of-Concept Study of Liposomes with a Set of SARS-CoV-2 Viral Peptidic T-Cell Epitopes as a Vaccine

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