Elevated serum 4HNE plus decreased serum thioredoxin: Unique feature and implications for acute exacerbation of chronic obstructive pulmonary disease

Abstract

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a global problem with high mortality. Its pathogenesis is not fully understood. To reveal new serum feature of AECOPD and their potential implications, we have analyzed 180 serum samples, and found that in the serum of AECOPD patients, 4-hydroxy-2-nonenal (4HNE)-protein adducts are dynamically increased as partial pressure of oxygen (PaO2) drops, which is accompanied by progressively decreasing thioredoxin reductase (TrxR1) and thioredoxin (Trx1), as compared with those of healthy people. This phenomenon is unique, because acute hypoxia patients have 1.1-fold or 1.7-fold higher serum TrxR1 or Trx1 activity, respectively, than healthy people, in keeping with low 4HNE level. Moreover, serum 4HNE-protein adducts may form disulfide-linked complexes with high-molecular-weight, the amount of which is significantly increased during AECOPD. Serum 4HNE-protein adducts include 4HNE-Trx1 adduct and 4HNE-TrxR1 adduct, but only the former is significantly increased during AECOPD. Through cell biology, biochemistry and proteomics methods, we have demonstrated that extracellular 4HNE and 4HNE-Trx1 adduct affect human bronchial epithelial cells via different mechanisms. 4HNE-Trx1 adduct may significantly alter the expression of proteins involved mainly in RNA metabolism, but it has no effect on TrxR1/Trx1 expression and cell viability. On the other hand, low levels of 4HNE promote TrxR1/Trx1 expression and cell viability, while high levels of 4HNE inhibit TrxR1/Trx1 expression and cell viability, during which Trx1, at least in part, mediate the 4HNE action. Our data suggest that increasing serum 4HNE and decreasing serum Trx1 in AECOPD patients are closely related to the pathological processes of the disease. This finding also provides a new basis for AECOPD patients to use antioxidant drugs.

Redox Regulation in Aging Lungs and Therapeutic Implications of Antioxidants in COPD

“…In addition to the negative effects of oxidative stress in the lungs, increased systemic ROS are detected, especially during COPD exacerbations, which are indicated by the increase in lipid peroxidation products and 4-hydroxynonenal (4-HNE) in the serum [ 103 , 104 ]. Although the detailed mechanisms underlying the comorbidities of COPD remain to be elucidated, ROS in combination with systemic inflammation are involved in the pathology of extrapulmonary manifestations, such as osteoporosis and skeletal muscle weakness, in patients with COPD [ 105 ].…”

“…These results suggest that the body attempts to neutralize excessive oxidative stress in COPD lungs by producing TRX. On the other hand, serum TRX levels are significantly decreased during acute exacerbations in patients with COPD accompanied by an increase in 4-hydroxynonenal (4-HNE) in serum [ 104 ], which suggests that systemic detrimental oxidative stress occurs by overwhelming the protective effects of TRX during acute exacerbations. Thus, these results suggest that tissue TRX levels are a good noninvasive marker of oxidative stress in patients with COPD and can be used to stratify patients with COPD for the identification of patient subpopulations who will benefit from antioxidant-targeting treatments.…”

Thioredoxin1 Binding Metastasis-Associated Lung Adenocarcinoma Transcript 1 Attenuates Inflammation and Apoptosis after Intracerebral Hemorrhage

“…Txn1 is a member of thioredoxins (Trxs) family and has been characterized as a guard of the intracellular redox state and antioxidants [7]. Previous studies have shown that Txn1 is involved in liver cancer, myocardial ischemia, pulmonary fibrosis, and brain diseases such as intracerebral infarction and Alzheimer's disease [8][9][10][11][12]. It mainly relieves oxidative stress in the central nervous system through Nrf2/Txn1/TXNIP [11] and other signal pathways, thus reducing brain injury.…”