Ivan Rodriguez-Oliveros

Background: Acute Respiratory Distress Syndrome (ARDS) is characterized by alveolar capillary damage that leads to inflammation and pulmonary edema.¹ The tissue injury causes a decrease in lung compliance, requiring patients to be mechanically ventilated. Approximately 23% of all ventilated patients are those with ARDS.¹ ARDS, classified through the Berlin consensus, is divided into three categories: mild, moderate, and severe. ARDS has a mortality rate of 30 to 45%, which varies based on severity.¹ Sepsis is the common cause of ARDS and is attributed to approximately 32% of cases.¹ Sepsis occurs when a significant inflammatory response to an infection causes tissue injury. Both sepsis and ARDS have a nonuniform immunogenic disease progression. Many of the current treatments are preventative or supportive care. The measures included early antibiotics, bed elevations, mechanical ventilation, and extracorporeal membrane oxygenation.² This systematic review aims to evaluate the potential of MSCs and MSC derivatives for improvement in managing sepsis-induced ARDS.

Methods: A PubMed database search was performed using the keywords “mesenchymal stromal cells,” “respiratory distress,” “inflammation”, and “sepsis,” with the exclusion criteria of studies published more than five years before this review.

Results: Key results emerged from the review focused on the safety and efficacy of MSC-derived exosomes and MSC treatments. First, a comparison of the sources of MSCs-derived exosomes revealed a favorable immunogenic response for adipose tissue, bone marrow, and umbilical cord derived exosomes.³ Adipose tissue-derived cells exhibited the most favorable response in treating sepsis-induced ARDS.³ Both MSC-derived exosome and MSC treatments exhibited anti-inflammatory properties that led to reduced lung edema and injury scores in in vivo animal studies.^3,5-6,8 MSC treatment derived from adipose tissue treatments was associated with decreased anticoagulant effect and decreased inotropic support through an in vivo study.⁶ MSC-derived exosomes showed decreased efficacy compared to MSC treatments.⁴ MSCs struggled to alleviate multisystem organ damage.⁴ The safety profile of MSCs indicated that they were safe in the short term, with data supporting safety at 1 year.⁷ Lastly, MSCs-derived exosome treatments combined with mitochondria produced a stronger response than by itself.⁸

Conclusion: These findings demonstrate the promising role of MCSs and MCS-derived exosomes in facilitating the treatment of Sepsis-induced ARDS. However, short study times, differing dosage intervals, and minimal human studies necessitate further research to refine treatment protocol regarding timing, dosage, and validation of efficacy translated from animal studies to clinical application.

Works Cited:

1. Byrnes D, Masterson CH, Artigas A, Laffey JG. Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med. 2021;42(1):20-39. doi:10.1055/s-0040-1713422
2. Geyer-Roberts E, Lacatusu DA, Kester J, Foster-Moumoutjis G, Sidiqi M. Preventative Management of Sepsis-Induced Acute Respiratory Distress Syndrome in the Geriatric Population. Cureus. 2023;15(2):e34680. Published 2023 Feb 6. doi:10.7759/cureus.34680
3. Deng H, Zhu L, Zhang Y, et al. Differential Lung Protective Capacity of Exosomes Derived from Human Adipose Tissue, Bone Marrow, and Umbilical Cord Mesenchymal Stem Cells in Sepsis-Induced Acute Lung Injury. Oxid Med Cell Longev. 2022;2022:7837837. Published 2022 Feb 27. doi:10.1155/2022/7837837
4. Homma K, Bazhanov N, Hashimoto K, et al. Mesenchymal stem cell-derived exosomes for treatment of sepsis. Front Immunol. 2023;14:1136964. Published 2023 Apr 26. doi:10.3389/fimmu.2023.1136964
5. Dos Santos CC, Amatullah H, Vaswani CM, et al. Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury [published correction appears in Eur Respir J. 2023 Nov 9;62(5):2054216. doi: 10.1183/13993003.54216-2020.]. Eur Respir J. 2022;59(1):2004216. Published 2022 Jan 6. doi:10.1183/13993003.04216-2020
6. Edström D, Niroomand A, Stenlo M, et al. Integrin α10β1-selected mesenchymal stem cells reduced hypercoagulopathy in a porcine model of acute respiratory distress syndrome. Respir Res. 2023;24(1):145. Published 2023 May 31. doi:10.1186/s12931-023-02459-6
7. Sitbon, A., Hauw-Berlemont, C., Mebarki, M., Heming, N., Mayaux, J., Diehl, J. L., Demoule, A., Annane, D., Marois, C., Demeret, S., Weiss, E., Voiriot, G., Fartoukh, M., Constantin, J. M., Mégarbane, B., Plantefève, G., Boucher-Pillet, H., Churlaud, G., Cras, A., Maheux, C., … APHP STROMA–CoV‐2 Collaborative Research Group (2024). Treatment of COVID-19-associated ARDS with umbilical cord-derived mesenchymal stromal cells in the STROMA-CoV-2 multicenter randomized double-blind trial: long-term safety, respiratory function, and quality of life. Stem cell research & therapy, 15(1), 109. https://doi.org/10.1186/s13287-024-03729-w
8. Lin KC, Fang WF, Yeh JN, et al. Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis. World J Stem Cells. 2024;16(6):690-707. doi:10.4252/wjsc.v16.i6.690