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Proc Natl Acad Sci U S A. 2019 Apr 10. pii: 201818522. doi: 10.1073/pnas.1818522116. [Epub ahead of print]

Regenerative therapy based on miRNA-302 mimics for enhancing host recovery from pneumonia caused by Streptococcus pneumoniae.

Wang Y1,2, Li Y2,3, Zhang P4,5, Baker ST6,7,8, Wolfson MR6,7,8, Weiser JN9, Tian Y10,5, Shen H11.

Author information

1
State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 510230 Guangzhou, China.
2
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
3
Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, 200025 Shanghai, China.
4
Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
5
Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
6
Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
7
Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
8
Temple Lung Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
9
Department of Microbiology, New York University School of Medicine, New York, NY 10016.
10
Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; ying.tian@temple.edu hshen@pennmedicine.upenn.edu.
11
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; ying.tian@temple.edu hshen@pennmedicine.upenn.edu.

Abstract

Bacterial pneumonia remains a leading cause of morbidity and mortality worldwide. A defining feature of pneumonia is lung injury, leading to protracted suffering and vulnerability long after bacterial clearance. Little is known about which cells are damaged during bacterial pneumonia and if the regenerative process can be harnessed to promote tissue repair and host recovery. Here, we show that infection of mice with Streptococcus pneumoniae (Sp) caused substantial damage to alveolar epithelial cells (AEC), followed by a slow process of regeneration. Concurrent with AEC regeneration, the expression of miRNA-302 is elevated in AEC. Treatment of Sp-infected mice with miRNA-302 mimics improved lung functions, host recovery, and survival. miRNA-302 mediated its therapeutic effects, not by inhibiting apoptosis and preventing damage, but by promoting proliferation of local epithelial progenitor cells to regenerate AEC. These results demonstrate the ability of microRNA-based therapy to promote AEC regeneration and enhance host recovery from bacterial pneumonia.

KEYWORDS:

alveolus; bacteria; miRNA; pneumonia; regeneration

PMID:
30971494
DOI:
10.1073/pnas.1818522116

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