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Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale

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Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale International Journal of Molecular Sciences Article Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale Maider Beitia 1,†, Diego Delgado 1,†, Pello Sánchez 1, Ana Vallejo de la Cueva 2,3 , José Ramón Cugat 4 and Mikel Sánchez 1,* 1 Advanced Biological Therapy Unit, Hospital Vithas Vitoria, 01008 Vitoria-Gasteiz, Spain; [email protected] (M.B.); [email protected] (D.D.); [email protected] (P.S.) 2 Care and Technology for Critical and Postcritical Patients Research Group, Bioaraba, 01009 Vitoria-Gasteiz, Spain; [email protected] 3 Intensive Care Unit, Araba University Hospital, Osakidetza Basque Health Service, 01009 Vitoria-Gasteiz, Spain 4 Pneumology Service, Sant Joan de Déu de Manresa Hospital, 08243 Manresa, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-945-252077 † M. Beitia and D. Delgado have contributed equally to this manuscript. Abstract: One of the most severe effects of coronavirus disease 2019 (COVID-19) is lung disorders Citation: Beitia, M.; Delgado, D.; such as acute respiratory distress syndrome. In the absence of effective treatments, it is necessary to Sánchez, P.; Vallejo de la Cueva, A.; search for new therapies and therapeutic targets. Platelets play a fundamental role in respiratory Cugat, J.R.; Sánchez, M. Platelet disorders resulting from viral infections, being the first line of defense against viruses and essential Lysate Nebulization Protocol for the in maintaining lung function. The direct application of platelet lysate (PL) obtained from the platelet- Treatment of COVID-19 and Its rich plasma of healthy donors could help in the improvement of the patient due its anti-inflammatory, Sequels: Proof of Concept and immunomodulatory, antifibrotic, and repairing effects. This work evaluates PL nebulization by Scientific Rationale. Int. J. Mol. Sci. analyzing its levels of growth factors and its biological activity on lung fibroblast cell cultures, 2021, 22, 1856. https://doi.org/ besides describing a scientific basis for its use in this kind of pathology. The data of the work 10.3390/ijms22041856 suggest that the molecular levels and biological activity of the PL are maintained after nebulization. Academic Editors: George Airway administration would allow acting directly on the lung tissue modulating inflammation and J. Kontoghiorghes, Christina stimulating reparative processes on key structures such as the alveolocapillary barrier, improving the N. Kontoghiorghe and disease and sequels. The protocol developed in this work is a first step for the study of nebulized PL Annita Kolnagou both in animal experimentation and in clinical trials. Received: 22 December 2020 Keywords: platelet-rich plasma; platelet lysate; COVID-19; nebulization; platelet; growth factors Accepted: 11 February 2021 Published: 12 February 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in A new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS- published maps and institutional affil- CoV-2) was identified in China at the end of 2019 [1]. It is transmitted by saliva droplets iations. and aerosols emitted by infected individuals [2]. People infected by this virus can progress either asymptomatically or develop the coronavirus disease 2019 (COVID-19) that can cause acute respiratory distress syndrome (ARDS) and/or cardiovascular complications among others which, in the most severe cases, might eventually lead to death [3–7]. Additionally, Copyright: © 2021 by the authors. COVID-19 frequently produces sequels such as pulmonary fibrosis, which progressively Licensee MDPI, Basel, Switzerland. reduces the respiratory capacity of patients and, hence, profoundly limits their quality of This article is an open access article life [8,9]. Lastly, it is important to take into consideration the complications that can arise distributed under the terms and when generating immunity, since as in the previous SARS-associated coronavirus, antibod- conditions of the Creative Commons ies against the patient’s own cells could be generated, developing immunopathological Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ disorders [10]. 4.0/). Int. J. Mol. Sci. 2021, 22, 1856. https://doi.org/10.3390/ijms22041856 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 18 can arise when generating immunity, since as in the previous SARS-associated corona- virus, antibodies against the patient’s own cells could be generated, developing immuno- pathological disorders [10]. While waiting for the effect of the new vaccines, there is no effective treatment to deal with this health emergency, and therefore, there is an urgent need for new treatments. The Int. J. Mol. Sci. 2021, 22, 1856 2 of 18 design of new therapies must be focused not only on the elimination of the virus but also on the recovery of the affected lung tissue and the avoidance or reduction of the severe sequels. In that sense, treatments based on regenerative medicine and specifically platelet- While waiting for the effect of the new vaccines, there is no effective treatment to rich plasma (PRP) could be suitable and effective to tackle this disease. deal with this health emergency, and therefore, there is an urgent need for new treatments. Platelet-rich plasma,The a designbiological of new therapy therapies approved mustbe by focused regulatory not onlyagencies, on the is elimination based of the virus on the concentration ofbut the also platelets on the recoverypresent in of theblood affected [11].lung Platelets tissue are and small the avoidance anucleate or reduction of the cells derived from megakaryocytessevere sequels. whose In that biosynthesis sense, treatments takes based place on in regenerative both bone marrow medicine and specifically and lungs [12,13]. Theirplatelet-rich actions rely plasma not only (PRP) on could the regulation be suitable of and thrombosis effective to but tackle also this on disease. the biological activity of thePlatelet-rich complex pool plasma, of chemokines, a biological therapy cytokines approved, and growth by regulatory factors agencies, is based released from the plateleton granules, the concentration which are of the able platelets to induce present biological in blood processes [11]. Platelets of pro- are small anucleate liferative, antifibrotic, andcells anti derived-inflammatory from megakaryocytes nature. Thus, whose they biosynthesis have been classically takes place con- in both bone marrow and lungs [12,13]. Their actions rely not only on the regulation of thrombosis but also sidered the principal responsible of hemostasis, wound healing, anti-inflammatory activ- on the biological activity of the complex pool of chemokines, cytokines, and growth ities, and tissue repair,factors among released others from [14] the. However, platelet granules, recent whichresearch are ableworks to induce have biologicalalso processes of shown an association ofproliferative, platelets with antifibrotic, antiviral andactivities anti-inflammatory as well as lung nature. biology Thus, and they phys- have been classically iology [15]. Even if plateletsconsidered are of the great principal importance responsible to activate of hemostasis, antiviral wound defense, healing, it has anti-inflammatory been revealed that virusesactivities, can al andso negatively tissue repair, affect among platelets others [by14 ].translating However, viral recent RNA research works have into proteins, which leadsalso to shown a conversion an association of healthy of platelets platelets with into antiviral detrimental activities ones as well [16] as. lung biology and Considering the mentionedphysiology pathophysiology [15]. Even if platelets generated are of great by COVID importance-19 and to activate other res- antiviral defense, it piratory infections, PRPhas-based been therapies revealed that could viruses counteract can also the negatively loss of affecthealthy platelets platelets by translating by viral RNA into proteins, which leads to a conversion of healthy platelets into detrimental ones [16]. a local administration of healthy donors’ platelet content and consequently, retrieve and Considering the mentioned pathophysiology generated by COVID-19 and other res- amplify their biologicalpiratory effects, infections,boosting the PRP-based regeneration therapies of damaged could counteract lung tissue the loss and of the healthy platelets by reduction of fibrosis. Asa localthat PRP administration must reach of healthythe alveoli donors’ in the platelet lungs, content we propose and consequently, its in- retrieve and haled application into theamplify respiratory their biological system by effects, the aspiration boosting theof allogenic regeneration nebulized of damaged PRP. lung tissue and Therefore, the aim of thisthe work reduction is to of develop fibrosis. a As protocol that PRP to must nebulize reach PRP the alveoli and to in evaluate the lungs, we propose its its composition and bioactivityinhaled application in order to into apply the respiratory it in COVID system-19 bypatients the aspiration to boost of the allogenic re- nebulized PRP. covery of the injured areaTherefore, as well the as aimto prevent of this work lung is fibrosis to develop sequels. a protocol In addition, to nebulize a scien- PRP and to evaluate its tific basis for its use in thiscomposition kind of pathologies and bioactivity is indescribed. order
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