The Therapeutic Effect of Extracellular Vesicles on Asthma in Pre-Clinical Models: A Systematic Review Protocol
Abstract
:1. Introduction
Objective of this Review
2. Experimental Section
2.1. Inclusion Criteria
2.1.1. Population
2.1.2. Intervention
- Any dose of EVs;
- Any type of EVs;
- Any isolation method of EVs;
- EVs isolated from any cell or animal;
- Any number of EV treatments (single, multiple);
- Any length of treatment (days, weeks, acute or chronic);
- Any form of EV delivery (co-culture or incubation with cells, targeted EV delivery using ligands or genetically modified vectors, intraperitoneal (ip), intravenous (iv), intramuscular (im)or subcutaneous (sc) injections, intranasal delivery, oral gavage);
- Any type of EV cargo (endogenous cargo such as miRNA, mRNA, protein, lipids, DNA, metabolites, or exogenous cargo where EVs were packaged with biologics including genetic material, recombinant proteins or pharmaceuticals).
2.1.3. Comparator
2.1.4. Study Design
2.1.5. Outcomes
- Inflammation. For in vivo models: changes in markers of inflammation including inflammatory mediators such as chemokines, cytokines, immunoglobulin E (IgE) levels, and white blood cell counts, measured using different methodologies such as Western blotting, enzyme-linked immunosorbent assays (ELISAs), mRNA, proteomics and multiplex arrays in bronchoalveolar lavage fluid (BALF). For in vitro/ex vivo models: measure markers of inflammation as described above but released by cells or ex vivo transplants in culture into the conditioned media.
- Airway hyperresponsiveness (AHR) measured by airway resistance and elastance or indices of airway smooth muscle contraction, such as measurement of cell stiffness or deformation, or contraction of ex vivo airway tissue preparations (e.g., thin-cut lung slices, airway rings or strips).
- Serum inflammation markers (measured by cytokines, total IgE levels, activation of peripheral blood mononuclear cells [PBMCs] including dendritic cells, T and B cells, monocytes, eosinophils, neutrophils, and natural killer cells).
- Airway remodelling as measured by: wall thickening, increased mass of airway smooth muscle, deposition and accumulation of extracellular matrix (ECM) proteins, goblet cell hyperplasia, and neo-vascularization of the airways.
- Molecular indices of cellular signaling that are linked to pro-asthma cellular responses (contraction measured by intracellular calcium influx in cultured human airway smooth muscle cells, NfκB or STAT signalling as a index of inflammation, SMAD activation, reactive oxygen species-mediated signalling, biosynthesis of ECM proteins) in all models.
2.2. Exclusion Criteria
- Original research published in a language other than English;
- Not published in the last 5 years;
- Experiments on lung disease/inflammation but not asthma;
- Studies on therapeutic strategies for allergic asthma that do not include EVs and/or EV-cargo;
- Studies on EVs causing asthma (pathogenic role);
- Research on liposomes or synthetic nanoparticles;
- Studies where EVs are not characterized according to MISEV guidelines;
- Non-primary studies e.g., reviews and systematic reviews, editorials, and opinion articles.
2.3. Review Team Members
2.4. Data Sources and Search Strategy
2.5. Study Selection Process
2.6. Dealing with Companion and Duplicate Publications
2.7. Data Extraction
- A data extraction document has been created on Microsoft Excel to extract data from selected studies (see Table 1). Two reviewers (POO and JEK) will independently extract the relevant data from the included articles. The list of variables for which outcome data will be extracted is detailed in the section below. Any discrepancies between the inclusion or exclusion decisions made by the two reviewers will be resolved by consensus through discussion, or adjudication by a third reviewer (AS), if necessary.
- Collection of study characteristics (author name, publication year, language of publication, country, study design, aim/conclusion of study, species/sex of control vs. intervention groups, sample size, outcome variables, and EV isolation, characterization, treatment methods).
- Outcome variables will be analyzed in relation to the change in the treatment group vs. the comparator group i.e., increase, decrease or no change in cytokines in treatment vs. control group. This is being done as there are a number of different assessment methodologies that can be used to measure the outcome variable. In this case, cytokine levels can be measured by Western blotting, ELISAs, mRNA, proteomics, or multiplex arrays. Furthermore, the data will also be compounded by the inclusion of in vitro, in vivo and ex vivo studies using different preclinical models. Lastly, different inflammatory mediators can be analyzed in each study. Therefore, outcome data will be extracted as an increase, decrease or no change in the treatment group vs. the comparator control group.
2.8. Dealing with Missing Data
2.9. Outcomes and Measures of Treatment Effect
2.10. Data Synthesis
2.11. Subgroup/Sensitivity Analysis
2.12. Risk of Bias Assessment
2.13. Publication Bias
3. Discussion
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Appendix A.1. Medline Search Strategy
exp Asthma/ |
asthma$.mp. |
(antiasthma$ or anti-asthma$).mp. |
Respiratory Sounds/ |
wheez$.mp. |
Bronchial Spasm/ |
bronchospas$.mp. |
(bronch$ adj3 spasm$).mp. |
bronchoconstrict$.mp. |
exp Bronchoconstriction/ |
(bronch$ adj3 constrict$).mp. |
Bronchial Hyperreactivity/ |
Respiratory Hypersensitivity/ |
((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp. |
((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp. |
or/1–15 |
exp Extracellular vesicles/ |
(extracellular vesic* or extra-cellular vesic* or small vesic* or exosom* or ectosome* or nanopartic* or nano-partic* or micropartic* or micro-partic* or exovesic* or exo-vesic* or microvesic* or micro-vesic* or evs or dexosom* or apopto* bod*).mp |
or/17–18 |
exp therapeutics/ |
(dt or pc or rh or th).fs |
(treat* or therap* or interven*).tw,kf |
or/20–22 |
16 and 19 and 23 |
limit 24 to (english language and yr = “2015 -Current”) |
* The asterisk serves as a wildcard symbol that broadens the search strategy by finding all the iterations of the word starting with the same letters. |
Appendix A.2. Scopus Search Strategy
TITLE-ABS-KEY(asthma* OR antiasthma* OR anti-asthma* OR wheez* OR bronchospasm* OR (bronch* W/3 spasm*) OR bronchoconstrict* OR (bronch* W/3 constrict*) OR ((bronchial* OR respiratory OR airway* OR lung*) W/3 (hypersensitiv* OR hyperreactiv* OR allerg* OR insufficiency)) OR ((dust OR mite*) W/3 (allerg* OR hypersensitiv*))) |
TITLE-ABS-KEY ((extracellular W/1 vesic*) OR (extra-cellular W/1 vesic*) OR (small W/1 vesic*) OR exosom* OR ectosome* OR nanopartic* OR nano-partic* OR micropartic* OR micro-partic* OR exovesic* OR exo-vesic* OR microvesic* OR micro-vesic* OR evs OR dexosom* OR (apopto* W/1 bod*)) |
TITLE-ABS-KEY(treat* OR therap* OR interven*) |
#1 AND #2 AND #3 |
#4 AND (LIMIT-TO (LANGUAGE, “English”) AND PUBYEAR > 2014 |
* The asterisk serves as a wildcard symbol that broadens the search strategy by finding all the iterations of the word starting with the same letters. |
Appendix A.3. EMBASE Search Strategy
exp Asthma/ |
asthma$.mp. |
(antiasthma$ or anti-asthma$).mp. |
Abnormal Respiratory Sound/ or Wheezing/ |
wheez$.mp. |
Bronchospasm/ |
bronchospas$.mp. |
(bronch$ adj3 spasm$).mp. |
bronchoconstrict$.mp. |
Bronchus Hyperreactivity/ |
(bronch$ adj3 constrict$).mp. |
Respiratory Tract Allergy/ |
((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp. |
House Dust Allergy/ |
((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp. |
or/1–15 |
exosome/ or exp membrane microparticle/ |
(extracellular vesic* or extra-cellular vesic* or small vesic* or exosom* or ectosom* or nanopartic* or nano-partic* or micropartic* or micro-partic* or exovesic* or exo-vesic* or microvesic* or micro-vesic* or evs or dexosom* or apopto* bod*).mp |
or/17-18 |
exp therapy/ |
dt.fs |
(treat* or therap* or interven*).tw,kw |
or/20–22 |
16 and 19 and 23 |
limit 24 to (english language and yr = “2015 -Current”) |
* The asterisk serves as a wildcard symbol that broadens the search strategy by finding all the iterations of the word starting with the same letters. |
Appendix A.4. Web of Science Search Strategy
TS = (asthma* OR antiasthma* OR anti-asthma* OR wheez* OR bronchospasm* OR (bronch* NEAR/3 spasm*) OR bronchoconstrict* OR (bronch* NEAR/3 constrict*) OR ((bronchial* OR respiratory OR airway* OR lung*) NEAR/3 (hypersensitiv* OR hyperreactiv* OR allerg* OR insufficiency)) OR ((dust OR mite*) NEAR/3 (allerg* OR hypersensitiv*))) |
TS = ((extracellular NEAR/1 vesic*) OR (extra-cellular NEAR/1 vesic*) OR (small NEAR/1 vesic*) OR exosom* OR ectosom* OR nanopartic* OR nano-partic* OR micropartic* OR micro-partic* OR exovesic* OR exo-vesic* OR microvesic* OR micro-vesic* OR evs OR dexosom* OR (apopto* NEAR/1 bod*)) |
TS = (treat* OR therap* OR interven*) |
#1 AND #2 AND #3 |
(#4 AND PY = (2015-2021)) AND LANGUAGE: (English) |
* The asterisk serves as a wildcard symbol that broadens the search strategy by finding all the iterations of the word starting with the same letters. |
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Data Extraction Variables | |
---|---|
Pubmed ID | Intervention: EV cargo |
Authors | Intervention: EV treatment dose |
Year of Publication | Intervention: EV treatment duration |
Country | Intervention: EV treatment frequency |
Publication Type (in vitro, in vivo, ex vivo) | Intervention: Number per independent intervention group (N) |
Study Design | Intervention: Route of EV delivery (ip, iv, im, sc, co-culture) |
Aim of the Study | |
Conclusion of the Study | Comparator |
Population: Species/type of cells | Primary Outcomes: Inflammation (in BALF and conditioned media) |
Population: Sex (cells/animal) | Primary Outcomes: AHR |
Population: Total number of animals used (N) | Secondary Outcomes: Serum inflammation markers |
Intervention: EV type | Secondary Outcomes: Airway remodelling |
Intervention: EV source | Secondary Outcomes: Molecular indices of cellular signalling |
Intervention: EV isolation method | Adherence to MISEV (Y/N) |
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Obi, P.O.; Kent, J.E.; Jeyaraman, M.M.; Askin, N.; Pierdoná, T.M.; Halayko, A.J.; Saleem, A. The Therapeutic Effect of Extracellular Vesicles on Asthma in Pre-Clinical Models: A Systematic Review Protocol. J. Respir. 2021, 1, 84-95. https://0-doi-org.brum.beds.ac.uk/10.3390/jor1010009
Obi PO, Kent JE, Jeyaraman MM, Askin N, Pierdoná TM, Halayko AJ, Saleem A. The Therapeutic Effect of Extracellular Vesicles on Asthma in Pre-Clinical Models: A Systematic Review Protocol. Journal of Respiration. 2021; 1(1):84-95. https://0-doi-org.brum.beds.ac.uk/10.3390/jor1010009
Chicago/Turabian StyleObi, Patience O., Jennifer E. Kent, Maya M. Jeyaraman, Nicole Askin, Taiana M. Pierdoná, Andrew J. Halayko, and Ayesha Saleem. 2021. "The Therapeutic Effect of Extracellular Vesicles on Asthma in Pre-Clinical Models: A Systematic Review Protocol" Journal of Respiration 1, no. 1: 84-95. https://0-doi-org.brum.beds.ac.uk/10.3390/jor1010009