TY - JOUR
TI - Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression
to attenuate sepsis-induced acute lung injury
AU - dos Santos, Claudia C.
AU - Amatullah, Hajera
AU - Vaswani, Chirag M. and
AU - Maron-Gutierrez, Tatiana
AU - Kim, Michael
AU - Mei, Shirley H. J. and
AU - Szaszi, Katalin
AU - Monteiro, Ana Paula T.
AU - Varkouhi, Amir K. and
AU - Herreroz, Raquel
AU - Angel Lorente, Jose
AU - Tsoporis, James N. and
AU - Gupta, Sahil
AU - Ektesabi, Amin
AU - Kavantzas, Nikolaos
AU - Salpeas,
AU - Vasileios
AU - Marshall, John C.
AU - Rocco, Patricia R. M.
AU - Marsden,
AU - Philip A.
AU - Weiss, Daniel J.
AU - Stewart, Duncan J.
AU - Hu, Pingzhao
AU - and Liles, W. Conrad
JO - European Respiratory Journal
PY - 2022
VL - 59
TODO - 1
SP - null
PB - EUROPEAN RESPIRATORY SOC JOURNALS LTD
SN - 0903-1936, 1399-3003
TODO - 10.1183/13993003.04216-2020
TODO - null
TODO - 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.
ER -