Περίληψη:
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.
Συγγραφείς:
dos Santos, Claudia C.
Amatullah, Hajera
Vaswani, Chirag M. and
Maron-Gutierrez, Tatiana
Kim, Michael
Mei, Shirley H. J. and
Szaszi, Katalin
Monteiro, Ana Paula T.
Varkouhi, Amir K. and
Herreroz, Raquel
Angel Lorente, Jose
Tsoporis, James N. and
Gupta, Sahil
Ektesabi, Amin
Kavantzas, Nikolaos
Salpeas,
Vasileios
Marshall, John C.
Rocco, Patricia R. M.
Marsden,
Philip A.
Weiss, Daniel J.
Stewart, Duncan J.
Hu, Pingzhao
and Liles, W. Conrad
