Protein Phosphatase 2A Reduces Cigarette Smoke-Induced Cathepsin S and Loss of Lung Function

Declan F. Doherty, Sridesh Nath, Justin Poon, Robert F Foronjy, Michael Ohlmeyer, Abdoulaye J Dabo , Matthias Salathe, Mark Birrell, Maria Belvisi, Nathalie Baumlin, Michael D Kim, Sinead Weldon, Clifford Taggart, Patrick Geraghty

Research output: Contribution to journalArticle

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Abstract

RATIONALE:
Cathepsin S (CTSS) is a cysteine protease that is observed at higher concentrations in bronchoalveolar lavage fluid and plasma of chronic obstructive pulmonary disease (COPD) subjects.

OBJECTIVES:
The objective of this study was to investigate whether CTSS is involved in the pathogenesis of cigarette smoke-induced COPD and determine whether targeting upstream signaling could prevent the disease.

METHODS:
CTSS expression was investigated in animal and human tissue and cell models of COPD. Ctss-/- mice were exposed to long-term cigarette smoke and forced oscillation and expiratory measurements were recorded. Animals were administered chemical modulators of protein phosphatase 2A (PP2A) activity.

MEASUREMENTS AND MAIN RESULTS:
Here we observed enhanced CTSS expression and activity in mouse lungs following exposure to cigarette smoke. Ctss-/- mice were resistant to cigarette smoke-induced inflammation, airway hyperresponsiveness, airspace enlargements and loss of lung function. CTSS expression was negatively regulated by PP2A in human bronchial epithelial cells isolated from healthy non-smokers and COPD donors and in monocyte-derived macrophages. Modulating PP2A expression or activity, with silencer short interfering RNA or a chemical inhibitor or activator, during acute smoke exposure in mice altered inflammatory responses and CTSS expression and activity in the lung. Enhancement of PP2A activity prevented chronic smoke-induced COPD in mice.

CONCLUSIONS:
Our study indicates that the decrease in PP2A activity that occurs in COPD contributes to elevated CTSS expression in the lungs and results in impaired lung function. Enhancing PP2A activity represents a feasible therapeutic approach to reduce CTSS activity and counter smoke-induced lung disease.
Original languageEnglish
Pages (from-to)51-62
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume200
Issue number1
Early online date14 Jan 2019
DOIs
Publication statusPublished - 01 Jul 2019

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