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J Clin Invest. 2019 Apr 15;130:2107-2122. doi: 10.1172/JCI125014. eCollection 2019 Apr 15.

Yap/Taz regulate alveolar regeneration and resolution of lung inflammation.

Author information

1
Department of Pharmacology, Center for Translational Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
2
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3
Department of Medicine, Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
4
Department of Medicine, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
5
Department of Physiology, Department of Thoracic Medicine and Surgery, Center for Inflammation, Translational and Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.

Abstract

Alveolar epithelium plays a pivotal role in protecting the lungs from inhaled infectious agents. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery from these insults in order to rebuild the epithelial barrier and restore pulmonary functions. Here, we show that sublethal infection of mice with Streptococcus pneumoniae, the most common pathogen of community-acquired pneumonia, led to exclusive damage in lung alveoli, followed by alveolar epithelial regeneration and resolution of lung inflammation. We show that surfactant protein C-expressing (SPC-expressing) alveolar epithelial type II cells (AECIIs) underwent proliferation and differentiation after infection, which contributed to the newly formed alveolar epithelium. This increase in AECII activities was correlated with increased nuclear expression of Yap and Taz, the mediators of the Hippo pathway. Mice that lacked Yap/Taz in AECIIs exhibited prolonged inflammatory responses in the lung and were delayed in alveolar epithelial regeneration during bacterial pneumonia. This impaired alveolar epithelial regeneration was paralleled by a failure to upregulate IκBa, the molecule that terminates NF-κB-mediated inflammatory responses. These results demonstrate that signals governing resolution of lung inflammation were altered in Yap/Taz mutant mice, which prevented the development of a proper regenerative niche, delaying repair and regeneration of alveolar epithelium during bacterial pneumonia.

KEYWORDS:

Adult stem cells; Bacterial infections; Pulmonology; Stem cells

PMID:
30985294
PMCID:
PMC6486331
[Available on 2019-08-01]
DOI:
10.1172/JCI125014
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