Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD

Abstract

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-kB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-kB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production.NRF expression, NF-kB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H 2 O 2 were used to elucidate the mechanisms.Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-kB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H 2 O 2 -decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs.NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.

Carbocisteine attenuates hydrogen peroxide-induced inflammatory injury in A549 cells via NF-κB and ERK1/2 MAPK pathways

“…Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide and is characterized by progressive airflow limitation associated with high levels of inflammatory mediators and marked oxidative stress, which can further promote the inflammatory process in COPD via enhancing NF-κB and/or MAPKdriven inflammatory gene transcription [1][2][3]. Oxidative stress and inflammation are inseparably intertwined in the pathogenesis of COPD.…”

Chronic Obstructive Pulmonary Disease in Stage I Non-small Cell Lung Cancer That Underwent Anatomic Resection: The Role of a Recurrence Promoter

“…A substantial number of studies have shown that a host environment with sustained infl ammation nurtures the initiation and progression of tumor cells (9)(10)(11). COPD, as one of the chronic morbidities featuring excessive circulating infl ammatory mediators such as interleukine (IL)-6, tumor necrosis factor (TNF)-α, IL-8 and activated leukocytes, well characterizes chronic systemic infl ammation (12)(13)(14).…”

The Respiratory Microbiome in COPD

“…In contrast, a reversal of this trend, i.e. an increase in microbial alpha diversity and microbial composition changes, has been observed when treatment of COPD exacerbation involves antibiotics (with or without steroids) [37,43]. Furthermore, this effect of antibiotic and steroid treatment on the microbiome structure appears to be prolonged, emphasising the importance of patient phenotype stratification.…”

“…It has a prominent role in COPD [42] whereby it induces airway inflammation by recruiting neutrophils and upregulating mucin genes, causing mucus production. As such, sputum CXCl8/IL-8 levels correlate well with COPD severity [43].…”