Dos Santos, Claudia C.Amatullah, HajeraVaswani, Chirag M.Maron Gutierrez, TatianaKim, MichaelMei, Shirley H.Szaszi, KatalinMonteiro, Ana PaulaLorente Balanza, José ÁngelLiles, ConradEt al.2022-09-112022-09-112022Dos Santos, C., Amatullah, H., Vaswani, C. M., Marón-Gutiérrez, T., Kim, M., Mei, S., Szaszi, K., Monteiro, A., Varkouhi, A., Herreroz, R., Lorente, J. A., Tsoporis, J. N., Gupta, S., Ektesabi, A., Kavantzas, N., Salpeas, V., Marshall, J. C., Rocco, P., Marsden, P. A., Weiss, D. J., … Liles, W. C. (2022). Mesenchymal Stromal (stem) Cell (MSC) therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury. The European Respiratory Journal, 59(1), 2004216. https://doi.org/10.1183/13993003.04216-20200903-19361399-3003http://hdl.handle.net/11268/11583Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3′ untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro. When administered in vivo, MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.engLesión pulmonarSepsisjournal article10.1183/13993003.04216-2020restricted accessCélulaEnfermedad cardiovascular