Abstract
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.
Abstract
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
Footnotes
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Author contributions: Concept and design: C.C. dos Santos, H. Amatullah, T. Maron-Gutierrez, P. Hu and W.C. Liles. Performed experiments and original data collection: H. Amatullah, C.M. Vaswani, T. Maron-Gutierrez, M. Kim, S.H.J. Mei, K. Szaszi, A.P.T. Monteiro, A.K. Varkouhi, R. Herreroz, J.A. Lorente, J.N. Tsoporis, N. Kavantzas, V. Salpeas, S. Gupta and A. Ektesabi. Data analysis and interpretation: H. Amatullah, P.A. Marsden, J.C. Marshall, P. Hu, P.R.M. Rocco, D.J. Weiss and C.C. dos Santos. Manuscript editing and discussion: D.J. Weiss, P.R.M. Rocco, P. Hu, J.C. Marshall, D.J. Stewart, H. Amatullah, W.C. Liles and C.C. dos Santos.
Conflict of interest: C.C. dos Santos has nothing to disclose.
Conflict of interest: H. Amatullah has nothing to disclose.
Conflict of interest: C.M. Vaswani has nothing to disclose.
Conflict of interest: T. Maron-Gutierrez has nothing to disclose.
Conflict of interest: M. Kim has nothing to disclose.
Conflict of interest: S.H.J. Mei has nothing to disclose.
Conflict of interest: K. Szaszi has nothing to disclose.
Conflict of interest: A.P.T. Monteiro has nothing to disclose.
Conflict of interest: A.K. Varkouhi has nothing to disclose.
Conflict of interest: R. Herreroz has nothing to disclose.
Conflict of interest: J.A. Lorente has nothing to disclose.
Conflict of interest: J.N. Tsoporis has nothing to disclose.
Conflict of interest: S. Gupta has nothing to disclose.
Conflict of interest: A. Ektesabi has nothing to disclose.
Conflict of interest: N. Kavantzas has nothing to disclose.
Conflict of interest: V. Salpeas has nothing to disclose.
Conflict of interest: J.C. Marshall reports personal fees for data monitoring committee work from AM Pharma, personal fees for advisory board work from Gilead Pharmaceuticals, outside the submitted work.
Conflict of interest: P.R.M. Rocco has nothing to disclose.
Conflict of interest: P.A. Marsden has nothing to disclose.
Conflict of interest: D.J. Weiss has nothing to disclose.
Conflict of interest: D.J. Stewart reports other (founding member, equity stake) from Northern Therapeutics, outside the submitted work.
Conflict of interest: P. Hu has nothing to disclose.
Conflict of interest: W.C. Liles has nothing to disclose.
Support statement: This work was supported by the Canadian Institutes of Health Research (grant number MOP-130331, MPO-106545 to C.C. dos Santos), the Canada Research Chair in Infectious Diseases and Inflammation to W.C. Liles, and the Ontario Research Fund (grant number RE07-086 to D.J. Stewart, S.H.J. Mei, W.C. Liles and C.C. dos Santos). H. Amatullah was the recipient of the Ontario Graduate Scholarship, St. Michael's Hospital Li Ka Shing Knowledge Institute Graduate Scholarship and Mary J. Santalo Fellowship. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 16, 2020.
- Accepted May 24, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org