PT  - JOURNAL ARTICLE
AU  - Claudia C. dos Santos
AU  - Hajera Amatullah
AU  - Chirag M. Vaswani
AU  - Tatiana Maron-Gutierrez
AU  - Michael Kim
AU  - Shirley H.J. Mei
AU  - Katalin Szaszi
AU  - Ana Paula T. Monteiro
AU  - Amir K. Varkouhi
AU  - Raquel Herreroz
AU  - Jose Angel Lorente
AU  - James N. Tsoporis
AU  - Sahil Gupta
AU  - Amin Ektesabi
AU  - Nikolaos Kavantzas
AU  - Vasileios Salpeas
AU  - John C. Marshall
AU  - Patricia R.M. Rocco
AU  - Philip A. Marsden
AU  - Daniel J. Weiss
AU  - Duncan J. Stewart
AU  - Pingzhao Hu
AU  - W. Conrad Liles
TI  - Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury
AID  - 10.1183/13993003.04216-2020
DP  - 2022 Jan 01
TA  - European Respiratory Journal
PG  - 2004216
VI  - 59
IP  - 1
4099  - http://erj.ersjournals.com/content/59/1/2004216.short
4100  - http://erj.ersjournals.com/content/59/1/2004216.full
SO  - Eur Respir J2022 Jan 01; 59
AB  - Although 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.The therapeutic effects of MSCs on polymicrobial sepsis-induced acute lung injury is mediated in part by regulation of recipient-derived miR-193b. This is important in human acute respiratory distress syndrome and may represent a new target for therapy. https://bit.ly/3ibZCOQ