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Reduction in polyamine catabolism leads to spermine‐mediated airway epithelial injury and induces asthma features
Author(s) -
Jain V.,
Raina S.,
Gheware A. P.,
Singh R.,
Rehman R.,
Negi V.,
Murray Stewart T.,
Mabalirajan U.,
Mishra A. K.,
Casero R. A.,
Agrawal A.,
Ghosh B.
Publication year - 2018
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.13472
Subject(s) - spermine , polyamine , apoptosis , polyamine oxidase , spermidine , chemistry , tunel assay , catabolism , gene knockdown , pharmacology , cancer research , microbiology and biotechnology , biochemistry , medicine , biology , enzyme
Background Airway epithelial injury is a crucial component of acute and severe asthma pathogenesis and a promising target for treatment of refractory asthma. However, the underlying mechanism of epithelial injury remains poorly explored. Although high levels of polyamines, mainly spermine, have been found in asthma and comorbidity, their role in airway epithelial injury and the cause of their altered levels in asthma have not been explored. Methods We measured key polyamine metabolic enzymes in lung samples from normal and asthmatic subjects and in mice with OVA ‐induced allergic airway inflammation ( AAI ). Polyamine metabolism was modulated using pharmacologic/genetic modulators. Epithelial stress and apoptosis were measured by TSLP levels and TUNEL assay, respectively. Results We found loss of the polyamine catabolic enzymes spermidine/spermine‐N (1)‐acetyltransferase‐1 ( SAT 1) and spermine oxidase ( SMOX ) predominantly in bronchial epithelial cells ( BEC s) of human asthmatic lung samples and mice with AAI . In naïve mice, SAT 1 or SMOX knockdown led to airway hyper‐responsiveness, remodeling, and BEC apoptosis. Conversely, in mice with AAI , overexpression of either SAT 1 or SMOX alleviated asthmatic features and reduced TSLP levels and BEC apoptosis. Similarly, while pharmacological induction of SAT 1 and SMOX using the polyamine analogue bis(ethyl)norspermine ( BENSPM ) alleviated asthmatic features with reduced TSLP levels and BEC apoptosis, pharmacological inhibition of these enzymes using BERENIL or MDL 72527, respectively, worsened them. Spermine accumulation in lungs correlated with BEC apoptosis, and spermine treatment caused apoptosis of human BEAS ‐2B cells in vitro. Conclusions Spermine induces BEC injury. Induction of polyamine catabolism may represent a novel therapeutic approach for asthma via reversing BEC stress.