Update on molecular mechanisms of corticosteroid resistance in chronic obstructive pulmonary disease

The review focuses on the role of interleukin-6 (IL-6) signaling in the development of a systemic inflammatory process in chronic obstructive pulmonary disease (COPD). In most researches the attention is paid to local inflammation in COPD. However, it is known that the pathology is characterized by a systemic inflammatory process, which is manifested in the increased levels of proinflammatory mediators in blood flow, and the study of the molecular mechanisms of its development is very important for the therapy of the disease. One of the key mediators of systemic inflammation is cytokine IL-6 which has pro- and antiinflammatory properties. Its effect on the cells is determined by the type of signaling. Nowadays three types of IL-6 signaling are identified: transsignaling, classical and cluster signaling. The review presents the known pathophysiological mechanisms of the development of systemic inflammation in COPD involving IL-6. As a proinflammatory cytokine, IL-6 performs the following functions: transmission of a signal on lung tissue damage, initiation of leukocyte migration into the inflammation site, inhibition of T-cell apoptosis into the inflammation site, influence on T helper differentiation, participation in pathophysiological reactions of development of emphysema and fibrosis. The significance of IL-6 transsignaling for the development of inflammation in COPD has been confirmed by many studies, while there are practically no works devoted to the study of classical IL-6 signaling in COPD. The data presented in the review indicate the need for further study of the role of different types of IL-6 signaling, especially classical signaling, in the regulation of systemic inflammation in COPD.

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Exploring the Pathogenesis and Potential Therapeutic Drugs of Chronic Obstructive Pulmonary Disease Based on Functional Disorder Modules

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2382 ◽

2021 ◽

Vol 11 (1) ◽

pp. 14-21

Author(s):

Hui Wang ◽

Yanliang Liu ◽

Zengjian Yang

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Molecular Mechanisms ◽

The United States ◽

Chronic Obstructive ◽

Nf Kappa B ◽

Obstructive Pulmonary Disease ◽

Humoral Immune ◽

Therapeutic Drugs ◽

Pathway Module

Researchers widely acknowledged that chronic obstructive pulmonary disease (COPD) became the third leading cause of death in the United States. At present, the pathogenesis and treatment of COPD still need to be further explored. In this study, the pathogenesis and treatment of COPD were modularized, and effective therapeutic drugs were explored. First, we identified 467 COPD-related genes from the NCBI-Gene database to explore the co-expression of these genes and their highly interacting proteins in patients with COPD. Secondly, COPD-related genes were analyzed using a co-expression module. Then, crosstalk analysis of co-expression modules was performed to reveal the interaction between these modules. Next, the enrichment of GO function and KEGG pathway module genes was analyzed. At the same time, non-coding RNAs (ncRNAs), transcription factors that regulate modules and potential drugs were predicted using hypergeometric tests. In summary, we obtained 22 co-expression modules, and a significant relationship was found between these modules. From the results of this study, we determined that the identified module genes are involved in the biological processes of cell growth, leukocyte activation, cytokine production, and humoral immune responses. Wnt, NF-kappa B, PI3 K-AKT, mitochondrial autophagy, oxidative stress, and other signaling pathways were significantly regulated. In addition, a ncRNA pivot (including microRNA-93-5p and microRNA-128-3p) and TF pivot (including NFKB1, RELA, and SP1) were identified as significant regulatory dysfunction modules. Finally, according to the target effect of drugs on the module genes, we found that drugs, such as fostamatinib and copper, demonstrate a certain therapeutic effect on COPD. In conclusion, COPD multifactorial dysfunction, in which helps to reveal the disease, at that meantime, to improve its basic molecular mechanisms. These findings provide valuable theoretical references for the diagnosis and personalized treatment of patients with COPD.

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The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology

Mediators of Inflammation ◽

10.1155/2018/1067134 ◽

2018 ◽

Vol 2018 ◽

pp. 1-22 ◽

Cited By ~ 10

Author(s):

Marta Stolarczyk ◽

Bob J. Scholte

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Cystic Fibrosis ◽

Pulmonary Disease ◽

Molecular Mechanisms ◽

Egf Receptor ◽

Airway Epithelial Cells ◽

Chronic Obstructive ◽

Lung Pathology ◽

Obstructive Pulmonary Disease ◽

Proinflammatory Mediators

Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated.

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Sirtuin 1 and Aging Theory for Chronic Obstructive Pulmonary Disease

Analytical Cellular Pathology ◽

10.1155/2015/897327 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 24

Author(s):

V. Conti ◽

G. Corbi ◽

V. Manzo ◽

G. Pelaia ◽

A. Filippelli ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Molecular Mechanisms ◽

The Elderly ◽

Sirtuin 1 ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Aging Theory ◽

New Biomarkers ◽

And Control

Chronic Obstructive Pulmonary disease (COPD) is an inflammatory syndrome that represents an increasing health problem, especially in the elderly population. Drug therapies are symptomatic and inadequate to contrast disease progression and mortality. Thus, there is an urgent need to clarify the molecular mechanisms responsible for this condition in order to identify new biomarkers and therapeutic targets. Processes including oxidant/antioxidant, protease/antiprotease, and proliferative/antiproliferative balance and control of inflammatory response become dysfunctional during aging as well as in COPD. Recently it was suggested that Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to oxidative stress and chronic inflammation, is implicated in both development and progression of COPD. The present review focuses on the involvement of SIRT1 in the regulation of redox state, inflammation, and premature senescence, all crucial characteristics of COPD phenotypes. Recent evidence corroborating the statement of the “aging theory for COPD” was also discussed.

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