Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale
Abstract
:1. Introduction
2. Results
2.1. Platelet-Rich Plasma Characterization
2.2. Growth Factor Profile in Standard and Nebulized Platelet-Rich Plasma
2.3. Impact of Platelet-Rich Plasma Nebulization on Its Bioactivity
3. Discussion
3.1. Role of Platelets against Viral Infections and SARS-CoV-2
3.2. The Importance of Platelets in Lung Biology
3.3. Therapeutic Potential of Platelet-Rich Plasma against COVID-19
4. Materials and Methods
4.1. Platelet-Rich Plasma Preparation
4.2. Platelet-Rich Plasma Lysate Nebulization
4.3. Enzyme-Linked Immunosorbent Assay (ELISA)
4.4. Cell Cultures and Culture Media
4.5. Cell Viability Assay
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
SARS-CoV-2 | Severe Acute Respiratory Syndrome Coronavirus 2 |
COVID-19 | Coronavirus Disease 2019 |
ARDS | Acute Respiratory Distress Syndrome |
PRP | Platelet-Rich Plasma |
PL | Platelet Lysate |
CCL-11 | C-C Motif Chemokine Ligand 11 (Eotaxin) |
CTGF | Connective Tissue Growth Factor |
HGF | Hepatocyte Growth Factor |
IGF-1 | Insulin-Like Growth Factor 1 |
PDGF | Platelet-Derived Growth Factor |
TGF-β | Transforming Growth Factor Beta |
VEGF | Vascular Endothelial Growth Factor |
GPiB | Glycoprotein Ib |
GPVI | Glycoprotein VI |
PRR | Pattern Recognition Receptors |
PAMP | Pathogen-Associated Molecular Pattern |
DAMP | Damage-Associated Molecular Pattern |
TLR | Tool-Like Receptor |
CLR | C-type Lectin Receptor |
DC-SIGN | Dendritic Cell-Specific ICAM3-Grabbing Non-Integrin |
ACE-2 | Angiotensin Converting Enzyme 2 |
NET | Neutrophil Extracellular Trap |
TMPRSS2 | Transmembrane protease, serine 2 |
ITGA2B | Integrin alpha-IIB |
CXCL4 | Platelet Factor 4 |
IL-1B | Interleukin 1-β |
MSC | Mesenchymal Stem Cells |
GM-CSF | Granulocyte-Macrophage Colony-Stimulating Factor |
ELISA | Enzyme-Linked Immunoabsorbent Assay |
MCP-1 | Monocyte Chemoattractant Protein-1 |
RNA | Ribonucleic Acid |
MPV | Mean Platelet Volume |
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1. Platelet-Rich Plasma Preparation | |
Initial blood volume | 10 mL |
Anticoagulant | Sodium citrate 3.8% (wt/V) |
System | Close |
Centrifugation | Yes |
number | 1 |
speed | 580× g—8 min |
Final PRP volume | 4 mL per subject |
2. Platelet-Rich Plasma Characteristics | |
PRP Type | 11-00-11 |
Mean Platelet Volume (MPV) | 9.6 ± 0.6 fL |
Red Blood Cells | <0.01 × 106/µL |
White Blood Cells | <0.05 × 106/µL |
Neutrophils | --- |
Lymphocytes | --- |
Monocytes | --- |
Eosinophils | --- |
Basophils | --- |
Activation | CaCl2 (10% wt/vol) |
3. Application Characteristics | |
Dose | 2% |
Direct/Indirect | Direct |
Cell line | Lung fibroblast |
4. Other Remarkable Platelet-Rich Plasma and Study Features | |
The product added to the cell cultures was the platelet lysate obtained after activation of PRP with calcium chloride (10%) |
Effectors | Target | Action | References |
---|---|---|---|
HGF, IGF-1, PDGF, TGF-β | NF-kB cellular pathway | Anti-inflammatory effect | [14,59,65] |
Platelet microparticles | Macrophages | Favoring the reparative phenotype M2 | [55] |
VEGF | Nrf2 cellular pathway | Preventing oxidative damage | [56] |
Sphingosine-1 | endothelial cells | Preserving alveolocapillary barrier | [43] |
PDGF, TGF-β, EGF, FGF-2, CTGF and other growth factors | Lung cell populations: fibroblast, endothelial and epithelial cells, alveolar Type II Cells | Cell migration and proliferation, and tissue repair | [57,62] |
VEGF-A/TGF-β1 | Fibroblast | Antifibrotic effect | [58,66] |
Type of Study | Target Cell/Tissue | Route of Administration | Effect | Reference |
---|---|---|---|---|
In vitro study | Airway epithelial cells | HGF at different concentrations in cell culture | Anti-apoptotic effect against pro-inflammatory stimuli | [69] |
In vivo study | Lung tissue in mice subjected to pneumonectomy | Platelet lysate administered intraperitoneally | Stimulation of adult mouse lung vascular and alveolar regeneration | [70] |
In vivo study | Lung tissue in mice treated with LPS to generate edema and ARDS | Platelet lysate administered intraperitoneally | Prevention of LPS-induced vascular leakage in lungs | [71] |
In vivo study | Horses with inflammatory airway disease | Intrabronchial instillation | Significative improvement of horses, with a reduction of the mucus grade and neutrophil amount | [72] |
Clinical study | Patients with inhalation lung injury | Aerosolized PRP | Lower extubation time, hospital stay and mortality rate | [73] |
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Beitia, M.; Delgado, D.; Sánchez, P.; Vallejo de la Cueva, A.; Cugat, J.R.; Sánchez, M. Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale. Int. J. Mol. Sci. 2021, 22, 1856. https://doi.org/10.3390/ijms22041856
Beitia M, Delgado D, Sánchez P, Vallejo de la Cueva A, Cugat JR, Sánchez M. Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale. International Journal of Molecular Sciences. 2021; 22(4):1856. https://doi.org/10.3390/ijms22041856
Chicago/Turabian StyleBeitia, Maider, Diego Delgado, Pello Sánchez, Ana Vallejo de la Cueva, José Ramón Cugat, and Mikel Sánchez. 2021. "Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale" International Journal of Molecular Sciences 22, no. 4: 1856. https://doi.org/10.3390/ijms22041856