Related Experiment Video
Updated: Jan 14, 2026
Intra-tracheal Administration of Haemophilus influenzae in Mouse Models to Study Airway Inflammation
Published on: March 2, 2016
Oxidative stress triggers Itch-mediated TXNIP degradation and NF-κB activation promoting chronic obstructive
Pei-Yun Lin1,2, Kang-Yun Lee3,4,5,6, Shu-Chuan Ho2,5
1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei , 110, Taiwan.
Background:
Chronic inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), are characterized by pulmonary structural changes, narrowing of the small airways, and destruction of the lung parenchyma caused by prolonged inflammation. Sustained inflammation mediated by macrophages is considered to play a critical role in COPD pathogenesis, while the inductive mechanisms of persistent inflammation remain unclear.
Methods:
In vitro, RAW264.7 cells were treated with cigarette smoke extract (CSE), hydrogen peroxide, and 12-O-tetradecanoylphorbol-13-acetate. Loss-of-function assays were performed using MAPK inhibitors and Itch-specific knockdown. In vivo, lung tissues from mice exposed to whole-body cigarette smoke (CS) for 12 weeks, as well as clinical samples from healthy non-smokers, a healthy smoker, and COPD patients, were analyzed.
Results:
Our findings demonstrated that thioredoxin-interacting protein (TXNIP) participates in CS-induced NF-κB activation in macrophages, which may contribute to pulmonary inflammation. CSE markedly inhibited TXNIP expression in RAW264.7 cells through MAPK-dependent regulation, accompanied by the induction of iNOS/NO and COX-2. The decrease in TXNIP was also detected in lung tissues and macrophages obtained from smoking mice, while higher NF-κB activation and lung inflammation occurred simultaneously. Additionally, CS-induced oxidative stress triggered MAPK-dependent proteasomal degradation of TXNIP, leading to subsequent NF-κB activation. The expression of E3 ligase Itch was elevated in smoking mouse lungs and in hydrogen peroxide-stimulated cells, whereas specific silencing Itch significantly attenuated TXNIP degradation as well as NF-κB activation. Moreover, Itch expression was increased in lung tissues, whereas TXNIP was markedly reduced in lung tissues, bronchoalveolar lavage fluid cells, and peripheral blood mononuclear cells from patients with COPD.
Conclusion:
Accordingly, CS-induced oxidative stress promotes Itch-mediated TXNIP degradation, leading to NF-κB-driven inflammation in macrophages and potentially contributing to COPD pathogenesis.
Insights
Cigarette smoke triggers oxidative stress, leading to Itch-mediated degradation of TXNIP. This process activates NF-κB, driving inflammation in macrophages and contributing to chronic obstructive pulmonary disease (COPD) development.
Area of Science:
- Pulmonary Medicine
- Immunology
- Molecular Biology
Background:
- Chronic inflammatory lung diseases like COPD involve lung structural changes and airway narrowing due to persistent inflammation.
- Macrophage-mediated inflammation is crucial in COPD pathogenesis, but the mechanisms driving sustained inflammation are not fully understood.
Purpose of the Study:
- To investigate the role of thioredoxin-interacting protein (TXNIP) in cigarette smoke-induced pulmonary inflammation.
- To elucidate the molecular mechanisms underlying TXNIP regulation and its contribution to COPD pathogenesis.
Main Methods:
- In vitro studies used RAW264.7 macrophages treated with cigarette smoke extract (CSE), hydrogen peroxide, and MAPK inhibitors.
- Loss-of-function assays included Itch-specific knockdown.
- In vivo studies analyzed lung tissues from mice exposed to cigarette smoke (CS) and clinical samples from healthy individuals and COPD patients.
Main Results:
- Cigarette smoke extract (CSE) inhibited TXNIP expression in macrophages via MAPK-dependent pathways, increasing iNOS/NO and COX-2.
- CS-induced oxidative stress promoted proteasomal degradation of TXNIP, mediated by the E3 ligase Itch, leading to NF-κB activation and inflammation.
- Reduced TXNIP and increased Itch expression were observed in lung tissues and cells from smoking mice and COPD patients.
Conclusions:
- Cigarette smoke-induced oxidative stress promotes Itch-mediated degradation of TXNIP.
- This degradation activates NF-κB signaling in macrophages, contributing to pulmonary inflammation.
- The Itch-TXNIP-NF-κB pathway represents a potential therapeutic target for COPD.
Related Concept Videos
01:20Chronic Obstructive Pulmonary Disease-II: Pathophysiology
Chronic Inflammation
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:20Chronic Obstructive Pulmonary Disease-I: Introduction
01:31Regulation of the Unfolded Protein Response
01:22Chronic Obstructive Pulmonary Disease
Smoking is a primary risk factor for COPD, with over 80% of patients having a history of it. Patients typically experience progressive dyspnea or labored breathing, frequent coughing, and recurrent pulmonary infections. Many eventually succumb to respiratory failure, characterized by...
01:26Asthma-II: Pathophysiology and Classification
Additionally, environmental and genetic factors play crucial roles in determining an individual's susceptibility to asthma and the severity of their condition.
Critical processes in asthma pathophysiology include: