Study on the Pathophysiological Importance of Txnip in Cigarette Smoke-Caused Pulmonary Inflammation and Chronic Obstructive Pulmonary Disease

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details


Chronic obstructive pulmonary disease (COPD) is the highest ranked airway disease among adults, which is characterized by the persistent and irreversible airflow limitation associated with an enhanced chronic pulmonary inflammation. Cigarette smoke-mediated oxidative stress and cytokine production serve as major predisposing factors of COPD. Thioredoxin-interacting protein (TXNIP) is an endogenous blocker of thioredoxin (Trx), while the loss of TXNIP effectively prompts Trx-mediated NF-κB activation in response to oxidative stress and cytokine stimulation. Our preliminary results showed that a decrease expression of TXNIP in cancer-associated COPD human lung biopsies compared to the normal human lung tissues. So far, the reduction of TXNIP involved in COPD progression has never been revealed. Therefore, in this proposed proposal, the pathophysiological importance of TXNIP in cigarette smoke-resulted NF-κB activation, pulmonary inflammation, and COPD progression will be first investigated. In Specific Aim 1, we will investigate the reduction of TXNIP facilitates cigarette smoke-evoked NF-κB activation and pro-inflammatory cytokine production. Preliminary results showed the decrease of TXNIP in smoking mice was associated with lung inflammation, oxidation, as well as NF-κB activation. The mechanisms of Itch-mediated TXNIP degradation, and the subsequent NF-κB activation, cytokine production under cigarette smoke will be verified in vivo and in vitro. In Specific Aim 2, we will identify the involvement of TLRs and NADPH Oxidase (NOX) in cigarette smoke-induced TXNIP degradation. Our unpublished data showed the degradation of TXNIP was markedly inhibited in TLR2-/- and NOX2-/- macrophages after bacterial infection. Accordingly, the regulatory importance of TLR and NOX2 signaling in cigarette smoke-induced TXNIP degradation will be investigated. In Specific Aim 3, we will demonstrate the exacerbated-pulmonary inflammation and COPD occurred in Txnip-/- mice under cigarette smoke. Basing on the results from aim 1 and aim 2, TXNIP is essential to negatively regulate NF-κB-mediated cytokine production and lung inflammation. Therefore, the exacerbated lung inflammation and COPD progression in Txnip-/- mice exposed to cigarette smoke will be determined. In Specific Aim 4, we will discover potential drugs that reverse cigarette smoke-induced TXNIP degradation and decline respiratory inflammation. The large screening of a nature compound library will be performed to look for potential novel compounds that can effectively inhibit cigarette smoke-mediated Itch/TXNIP-dependent or -independent NF-κB activation and cytokine production. The effective compounds will be further applied to in vivo, by which the progression of COPD in smoking mice will be declined after appropriate treatments. By these evidences provided from this proposal, we will demonstrate the pathological importance of TXNIP in cigarette smoke-resulted pulmonary inflammation and COPD, meanwhile, we will also provide a new therapeutic strategy against COPD.
Effective start/end date8/1/177/31/18


  • cigarette smoke
  • ROS
  • NF-κB
  • pulmonary inflammation
  • COPD


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