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Signaling of oxidative stress activated by cigarette smoke. Cigarette smoke induces oxidative signaling and inflammatory responses. In this respect, cigarette smoke induces ROS production and impairs CFTR function, which is also a trigger of oxidative stress to activate the dioxin receptor-mediated signaling pathway and induce ROS production and cell cycle arrest or apoptosis and other signaling pathways.
Source publication
Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. Cigarette smoke and oxidative stress are main etiological risks in COPD. Interestingly, recent studies suggest a considerable overlap between chronic bronchitis (CB) phenotypic COPD and cystic fibrosis (CF), a common fat...
Citations
... Although COP, ACO and CF have some phenotypically associated clinical features such as chronic airway inflammation, recurrent infectious exacerbations, mucus hypersecretion, and impaired mucociliary clearance, they also share some key functional features such as progressive airflow obstruction, pulmonary hyperinflation, trapped gases and gas exchange disturbances, and hence that may suggest the existence of common mechanisms [63][64][65][66]. All three diseases have always been treated as unrelated, distinct entities. ...
The objectives of the present study were to evaluate the discriminating power of spirometric and plethysmographic lung function parameters to differenciate the diagnosis of asthma, ACO, COPD, and to define functional characteristics for more precise classification of obstructive lung diseases. From the databases of 4 centers, a total of 756 lung function tests (194 healthy subjects, 175 with asthma, 71 with ACO, 78 with COPD and 238 with CF) were collected, and gradients among combinations of target parameters from spirometry (forced expiratory volume one second: FEV 1 ; FEV 1 /forced vital capacity: FEV 1 /FVC; forced expiratory flow between 25–75% FVC: FEF 25-75 ), and plethysmography (effective, resistive airway resistance: sR eff ; aerodynamic work of breathing at rest: sWOB), separately for in- and expiration (sR eff IN , sR eff EX , sWOB in , sWOB ex ) as well as static lung volumes (total lung capacity: TLC; functional residual capacity: FRC pleth ; residual volume: RV), the control of breathing (mouth occlusion pressure: P 0.1 ; mean inspiratory flow: V T /T I ; the inspiratory to total time ratio: T I /T tot ) and the inspiratory impedance (Z in pleth = P 0.1 /V T /T I ) were explored. Linear discriminant analyses (LDA) were applied to identify discriminant functions and classification rules using recursive partitioning decision trees. LDA showed a high classification accuracy (sensitivity and specificity > 90%) for healthy subjects, COPD and CF. The accuracy dropped for asthma (~70%) and even more for ACO (~60%). The decision tree revealed that P 0.1 , sR tot , and V T /T I differentiate most between healthy and asthma (68.9%), COPD (82.1%), and CF (60.6%). Moreover, using sWOB ex and Z in pleth ACO can be discriminated from asthma and COPD (60%). Thus, the functional complexity of obstructive lung diseases can be understood, if specific spirometric and plethysmographic parameters are used. Moreover, the newly described parameters of airway dynamics and the central control of breathing including Z in pleth may well serve as promising functional marker in the field of precision medicine.
... This information may help personalize treatment and improve patient outcomes by adjusting therapies to genetics. Numerous genetic investigations have found COPD susceptibility genes, such as α1-antitrypsin deficiency, smoking-induced CFTR failure, and newly discovered genes [131][132][133]. Genes linked to the pathophysiology of COPD have been linked to the condition's possible association and provide unique insights into the development and severity of the disease [132]. ...
... Numerous genetic investigations have found COPD susceptibility genes, such as α1-antitrypsin deficiency, smoking-induced CFTR failure, and newly discovered genes [131][132][133]. Genes linked to the pathophysiology of COPD have been linked to the condition's possible association and provide unique insights into the development and severity of the disease [132]. Additionally, the prevention and treatment of COPD depend on the identification and prioritization of COPD candidate genes [134]. ...
Background
According to the increasing trend of COPD, the timely diagnosis and treatment of the disease can reduce the high costs to the health systems. Therefore, by biological calculation methods, signaling pathways and genes involved in this disease can be obtained and used to design drugs and other treatment methods. By using biological calculations, we determined that curcumin can affect this disease and its genes and signaling pathways. Our goal in this study was to find the genes by which curcumin exerts its effect and can maintain the function of corticosteroids against oxidizing agents.
Results
By finding the genes, it is possible to find precisely the pathways by which curcumin works, which can be used to design other drugs that cause these pathways and minimize their side effects. This study considers healthy samples (with/without curcumin) and oxygen-free radicals (with/without curcumin). Finally, statistical algorithms extract meaningful genes as effective biomarkers to investigate curcumin's effects and signaling pathways in COPD. The results show that the genes finally obtained as the most critical genes confirmed by the literature are effective in COPD. Finally, curcumin was input in SwissTargetPrediction to identify potential protein receptors. We used LigPlot+ software to visualize the receptor–ligand binding result provided by iGEMDOCK.
Conclusions
The data showed that the most significant genes in each group have been confirmed in other studies to be effective in this disease, and protein–protein interaction networks can be established between them to investigate their roles.
... Recent in vitro and in vivo findings have determined that COPD is considered an obstructive lung disease due to acquired deficiency of CFTR. Mechanistically, CS-induced oxidative stress and increased cytosolic Ca 2+ levels as well as CS toxic components, which are considered the major causes of COPD, can lead to reduced CFTR levels in airway epithelia [63]. CFTR loss/dysfunction is due to multiple mechanisms, including reduced CFTR transcription, diminished CFTR protein by heightened protein degradation, and an increase in its internalization rate followed by the retrograde trafficking of CFTR to the endoplasmic reticulum [64][65][66][67]. ...
... Moreover, CS could also alter CFTR lipid rafts in macrophages, impairing bacterial phagocytosis and killing activity [71]. Overall, these findings suggest that, as in CF, the first steps in COPD pathogenesis (especially regarding CB) are represented by impaired ion and liquid homeostasis, mucociliary clearance reduction, and the ensuing opportunistic infection and inflammation [63]. However, the COPD pathogenesis of early as well of chronic disease is not well known, leaving room for other pathomechanisms to be found and studied. ...
In keeping with the extraordinary interest and advancement of extracellular vesicles (EVs) in pathogenesis and diagnosis fields, we herein present an update to the knowledge about their role in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Although CF and COPD stem from a different origin, one genetic and the other acquired, they share a similar pathophysiology, being the CF transmembrane conductance regulator (CFTR) protein implied in both disorders. Various subsets of EVs, comprised mainly of microvesicles (MVs) and exosomes (EXOs), are secreted by various cell types that are either resident or attracted in the airways during the onset and progression of CF and COPD lung disease, representing a vehicle for metabolites, proteins and RNAs (especially microRNAs), that in turn lead to events as such neutrophil influx, the overwhelming of proteases (elastase, metalloproteases), oxidative stress, myofibroblast activation and collagen deposition. Eventually, all of these pathomechanisms lead to chronic inflammation, mucus overproduction, remodeling of the airways, and fibrosis, thus operating a complex interplay among cells and tissues. The detection of MVs and EXOs in blood and biological fluids coming from the airways (bronchoalveolar lavage fluid and sputum) allows the consideration of EVs and their cargoes as promising biomarkers for CF and COPD, although clinical expectations have yet to be fulfilled.
... Panel (e) represents the method for measurement anatomy and physiology share common features with humans [31]. Our data could have important implications in CF as well, since recent studies suggest substantial overlap between COPD and CF due to CFTR dysfunction [1,2,11,12,17,33]. Hypertonic NaCl has long been used in the treatment of CF and is known to improve lung function and to have marked benefits regarding exacerbations [25,[34][35][36]. ...
Background
Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are often associated with airway fluid acidification. Mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene leads to impaired bicarbonate secretion contributing to CF airway pathology. Chronic cigarette smoke (CS) -the major cause of COPD- is reported to induce acquired CFTR dysfunction underlying airway acidification and inflammation. We hypothesize that bicarbonate-containing aerosols could be beneficial for patients with CFTR dysfunctions. Thus, we investigated the safety of hypertonic sodium bicarbonate (NaHCO 3 ) inhalation in CS-exposed guinea pigs.
Methods
Animals were divided into groups inhaling hypertonic NaCl (8.4%) or hypertonic NaHCO 3 (8.4%) aerosol for 8 weeks. Subgroups from each treatment groups were further exposed to CS. Respiratory functions were measured at 0 and after 2, 4, 6 and 8 weeks. After 8 weeks blood tests and pulmonary histopathological assessment were performed.
Results
Neither smoking nor NaHCO 3 -inhalation affected body weight, arterial and urine pH, or histopathology significantly. NaHCO 3 -inhalation did not worsen respiratory parameters. Moreover, it normalized the CS-induced transient alterations in frequency, peak inspiratory flow, inspiratory and expiratory times.
Conclusion
Long-term NaHCO 3 -inhalation is safe in chronic CS-exposed guinea pigs. Our data suggest that bicarbonate-containing aerosols might be carefully applied to CF patients.
... 238 ROS impaired the expression and function of CTFR, which was another contributor to CS in COPD. 239 Notably, CTFR dysfunction could be reversed by S-nitrosoglutathione, which restored autophagy impairment and alleviated chronic inflammatory-OS in CS-induced COPD. 240 Consistently, insufficient mitophagy resulted in PTEN-induced putative protein kinase 1 (PINK1) accumulation and parkin RBR E3 ubiquitin protein ligase reduction via PINK1-mediated proteasomal degradation, which further accelerated insufficient mitophagy and ROS release, becoming a significant inducer of COPD pathogenesis. ...
Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double‐edged sword in disease progression suggest two different therapeutic strategies to treat redox‐relevant diseases, in which targeting ROS sources and redox‐related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox‐relevant diseases. Redox homeostasis is essential for human health, supported by multiple functional signaling pathways including the Keap1‐Nrf2, FOXO, HIF and NF‐κB pathways. However, redox imbalance causes multiple serious diseases such as type 2 diabetes, atherosclerosis, chronic obstructive pulmonary disease, Alzheimer's disease, cancer, and aging. Our review emphasizes the significance of redox manipulation in clinical therapeutics and points out the existing challenges involved in this field.
... 27 The expression as well as the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is impaired during OS, thus contributing to the progression of airway dysfunctions, including chronic obstructive pulmonary disease (COPD), consequent to alteration of the mucociliary transport in airway epithelial cells. 28 On the other hand, CFTR is permeable to not only chloride ions, but also organic anions such as reduced glutathione, and consequently CFTR dysfunction potently contributes to the OS burden at the airway surface in cystic fibrosis. 29 Recent studies have established that the Na + /K + -ATPase can cause OS with mechanisms distinct from its wellunderstood function of ion pump but rather dependent on the scaffolding properties of the alpha1 subunit, which is targeted by OS and post-translationally modified, thus leading to the activation of a downstream signalling cascade eventually amplifying ROS production. ...
Bicarbonate is one of the major anions in mammalian tissues and fluids, is utilized by various exchangers to transport other ions and organic substrates across cell membranes and plays a critical role in cell and systemic pH homeostasis. Chloride/bicarbonate (Cl−/HCO3−) exchangers are abundantly expressed in erythrocytes and epithelial cells and, as a consequence, are particularly exposed to oxidants in the systemic circulation and at the interface with the external environment. Here, we review the physiological functions and pathophysiological alterations of Cl−/HCO3− exchangers belonging to the solute carriers SLC4 and SLC26 superfamilies in relation to oxidative stress. Particularly well studied is the impact of oxidative stress on the red blood cell SLC4A1/AE1 (Band 3 protein), of which the function seems to be directly affected by oxidative stress and possibly involves oxidation of the transporter itself or its interacting proteins, with detrimental consequences in oxidative stress‐related diseases including inflammation, metabolic dysfunctions, and aging. The effect of oxidative stress on SLC26 members was less extensively explored. Indirect evidence suggests that SLC26 transporters can be target as well as determinants of oxidative stress, especially when their expression is abolished or dysregulated.
... The acquired CFTR alteration in COPD is well described [15]. Briefly, the association of COPD with CFTR dysfunction relies on three main associations: the direct implication of tobacco smoke and the relationship between oxidative stress and CFTR physiology, as well as CFTR mutations. ...
In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.
... Along with the genetic mechanism of CFTR dysfunction present in CF that can impair autophagy, CFTR function has been shown to be diminished by CS exposure [40,[107][108][109], which is known as acquired CFTR dysfunction. One mechanism of CS-induced CFTR dysfunction leading to impaired autophagy is through increased ceramide accumulation as a result of altered sphingolipid homeostasis in COPD patients [22,93,110]. ...
... Specifically, a decrease in/loss of WT-CFTR is causally related to increased ROS-mediated inflammatory-oxidative stress, mucus hypersecretion, elevated ceramide levels, and hampered mucociliary clearance resulting in an increased incident of recurrent and chronic pulmonary infections, all of which result in chronic obstructive pathologies in CF airways [15,51,53,110,194]. It is now well documented that CS exposure [22,40,63,107,108], eCV [39,195], or certain infectious agents [196][197][198] also induce a decrease in the activity or expression of CFTR in the airways and was aptly described as acquired CFTR dysfunction. As expected, CS-induced ROS and the resulting oxidative stress was found to be the main cause of acquired CFTR dysfunction in COPD [62,[107][108][109]. ...
... It is now well documented that CS exposure [22,40,63,107,108], eCV [39,195], or certain infectious agents [196][197][198] also induce a decrease in the activity or expression of CFTR in the airways and was aptly described as acquired CFTR dysfunction. As expected, CS-induced ROS and the resulting oxidative stress was found to be the main cause of acquired CFTR dysfunction in COPD [62,[107][108][109]. Moreover, the mechanistic confirmation of the role of acquired CFTR dysfunction in COPD pathogenesis comes from studies which showed that the pharmacological rescue of mutant CFTR to the PM was able to correct CS-induced inflammatory-oxidative stress, autophagy impairment, and COPD-emphysema pathogenesis [14,42,62]. ...
The preservation of cellular homeostasis requires the synthesis of new proteins (proteostasis) and organelles, and the effective removal of misfolded or impaired proteins and cellular debris. This cellular homeostasis involves two key proteostasis mechanisms, the ubiquitin proteasome system and the autophagy–lysosome pathway. These catabolic pathways have been known to be involved in respiratory exacerbations and the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and coronavirus disease-2019 (COVID-19). Briefly, proteostasis and autophagy processes are known to decline over time with age, cigarette or biomass smoke exposure, and/or influenced by underlying genetic factors, resulting in the accumulation of misfolded proteins and cellular debris, elevating apoptosis and cellular senescence, and initiating the pathogenesis of acute or chronic lung disease. Moreover, autophagic dysfunction results in an impaired microbial clearance, post-bacterial and/or viral infection(s) which contribute to the initiation of acute and recurrent respiratory exacerbations as well as the progression of chronic obstructive and restrictive lung diseases. In addition, the autophagic dysfunction-mediated cystic fibrosis transmembrane conductance regulator (CFTR) immune response impairment further exacerbates the lung disease. Recent studies demonstrate the therapeutic potential of novel autophagy augmentation strategies, in alleviating the pathogenesis of chronic obstructive or restrictive lung diseases and exacerbations such as those commonly seen in COPD, CF, ALI/ARDS and COVID-19.
... The antecedent of smoking in patients with PNTM has been reported [32, 86,189,190]. Smoking impairs the immune defences at the respiratory level by different mechanisms such as inhibition of bacterial killing due to bacterial phagocytosis defects, modulating CFTR dependent lipid-rafts and autophagy impairment, among others [191][192][193][194][195][196]. The predisposing role of smoking in PNTM could be mediated by direct effect on the immune response and indirectly, by its association with pathologies that increase the risk of PNTM such as COPD [196,197]. ...
... Alcohol abuse has been associated with the risk of PNTM in HIV infected and non-infected individuals [190,193]. ...
Currently, there is a trend of increasing incidence in pulmonary non-tuberculous mycobacterial infections (PNTM) together with a decrease in tuberculosis (TB) incidence, particularly in developed countries. The prevalence of PNTM in underdeveloped and developing countries remains unclear as there is still a lack of detection methods that could clearly diagnose PNTM applicable in these low-resource settings. Since non-tuberculous mycobacteria (NTM) are environmental pathogens, the vicinity favouring host-pathogen interactions is known as important predisposing factor for PNTM. The ongoing changes in world population, as well as socio-political and economic factors, are linked to the rise in the incidence of PNTM. Development is an important factor for the improvement of population well-being, but it has also been linked, in general, to detrimental environmental consequences, including the rise of emergent (usually neglected) infectious diseases, such as PNTM. The rise of neglected PNTM infections requires the expansion of the current efforts on the development of diagnostics, therapies and vaccines for mycobacterial diseases, which at present, are mainly focused on TB. This review discuss the current situation of PNTM and its predisposing factors, as well as the efforts and challenges for their control.
... Reasons for a loss of CFTR mRNA expression include promoter hypermethylation as has been reported in lung, breast, head and neck, and bladder cancer studies [34][35][36][37][38] and somatic CFTR mutations as seen in NSCLC [32]. Furthermore, cigarette smoke (CS) was reported to downregulate CFTR mRNA expression and downregulation of CFTR expression has been associated with the development of chronic obstructive pulmonary disease (COPD) [136]. A link ...
... Reasons for a loss of CFTR mRNA expression include promoter hypermethylation as has been reported in lung, breast, head and neck, and bladder cancer studies [34][35][36][37][38] and somatic CFTR mutations as seen in NSCLC [32]. Furthermore, cigarette smoke (CS) was reported to downregulate CFTR mRNA expression and downregulation of CFTR expression has been associated with the development of chronic obstructive pulmonary disease (COPD) [136]. A link between CS, downregulation of CFTR, and lung cancer was reported in a study that correlated CS and CFTR downregulation with enhanced oncogenesis in A549 lung cancer cells [137]. ...
Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/β-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.
