Targeting lysyl oxidase like 2 attenuates OVA-induced airway remodeling partly via the AKT signaling pathway.

Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 101090633 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-993X (Electronic) Linking ISSN: 14659921 NLM ISO Abbreviation: Respir Res Subsets: MEDLINE

Publication: 2001- : London : BioMed Central Ltd.
Original Publication: London : Current Science Ltd., c2000-

Amino Acid Oxidoreductases*/metabolism ; Amino Acid Oxidoreductases*/genetics ; Amino Acid Oxidoreductases*/biosynthesis ; Ovalbumin*/toxicity ; Airway Remodeling*/physiology ; Proto-Oncogene Proteins c-akt*/metabolism ; Asthma*/pathology ; Asthma*/metabolism ; Asthma*/enzymology ; Asthma*/genetics ; Signal Transduction*/physiology; Animals ; Mice ; Humans ; Female ; Mice, Inbred BALB C ; Male ; Epithelial-Mesenchymal Transition/physiology

Background: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma.
Methods: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor.
Results: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-β1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression.
Conclusions: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.
(© 2024. The Author(s).)

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Keywords: Airway remodeling; Asthma; EMT; Extracellular matrix; LOXL2

EC 1.4.- (Amino Acid Oxidoreductases)
9006-59-1 (Ovalbumin)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 1.4.3.- (LOXL2 protein, human)
EC 1.4.3.- (Loxl2 protein, mouse)

Date Created: 20240602 Date Completed: 20240602 Latest Revision: 20240611

20240611

PMC11144323

10.1186/s12931-024-02811-4

38824593