Differential roles for lysyl oxidase (like), family members in chronic obstructive pulmonary disease; from gene and protein expression to function: from gene and protein expression to function

Nataliya Migulina*, Gavin Tjin, Alen Faiz, Theo Borghuis, Fenghua Zhao, Hans J Kaper, Marit Metzlar, Eline van Dijk, Prashant K Sharma, Wim Timens, Reinoud Gosens, Corry-Anke Brandsma, Janette K Burgess

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by long-term airflow obstruction with cigarette smoke as a key risk factor. Extracellular matrix (ECM) alterations in COPD may lead to small airway wall fibrosis. Altered collagen cross-linking, potentially mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4), orchestrates disturbed ECM homeostasis. In this study, we investigated the effects of smoking status and presence and severity of COPD on LOs gene and protein expression in the airways and the impact of LOs inhibition on airway contraction in an ex vivo mouse model. We used gene expression data from bronchial brushings, airway smooth muscle (ASM) cells in vitro and immunohistochemistry in lung tissue to assess smoke- and COPD-associated differences in LOs gene and protein expression in the small airways. We found higher LOX expression in current- compared to ex-smokers and higher LOXL1 expression in COPD compared to non-COPD patients. LOX and LOXL2 expression were upregulated in COPD ASM cells treated with cigarette smoke extract. LOXL1 and LOXL2 protein levels were higher in small airways from current- compared to non-smokers. In COPD patients, higher LOXL1 and lower LOX protein levels were observed, but no differences for LOXL2, LOXL3, and LOXL4 protein were detected in small airways. Inhibiting LOs activity increased airway contraction in murine lung slices. COPD-associated changes in LOs, in particular LOX and LOXL1, may be related to smoking and contribute to impaired airway function, providing potential novel targets for preventing or treating small airways changes in COPD.

Original languageEnglish
Article number22374
Number of pages16
JournalThe FASEB Journal
Volume36
Issue number7
DOIs
Publication statusPublished - Jul-2022

Keywords

  • collagen
  • COPD
  • ECM
  • lysyl oxidase
  • smoking
  • COLLAGEN
  • LUNG
  • STIFFNESS
  • INHIBITION
  • EMPHYSEMA
  • LOX

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