scholarly journals Cigarette Smoke Exposure Induces Retrograde Trafficking of CFTR to the Endoplasmic Reticulum

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Abigail J. Marklew ◽  
Waseema Patel ◽  
Patrick J. Moore ◽  
Chong D. Tan ◽  
Amanda J. Smith ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cigarette Smoke ◽  
Anion Channel ◽  
Airway Disease ◽  
Underlying Mechanism ◽  
The Body ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Retrograde Trafficking ◽  
Anion Secretion

Abstract Chronic obstructive pulmonary disease (COPD), which is most commonly caused by cigarette smoke (CS) exposure, is the third leading cause of death worldwide. The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane anion channel that is widely expressed in epithelia throughout the body. In the airways, CFTR plays an important role in fluid homeostasis and helps flush mucus and inhaled pathogens/toxicants out of the lung. Inhibition of CFTR leads to mucus stasis and severe airway disease. CS exposure also inhibits CFTR, leading to the decreased anion secretion/hydration seen in COPD patients. However, the underlying mechanism is poorly understood. Here, we report that CS causes CFTR to be internalized in a clathrin/dynamin-dependent fashion. This internalization is followed by retrograde trafficking of CFTR to the endoplasmic reticulum. Although this internalization pathway has been described for bacterial toxins and cargo machinery, it has never been reported for mammalian ion channels. Furthermore, the rapid internalization of CFTR is dependent on CFTR dephosphorylation by calcineurin, a protein phosphatase that is upregulated by CS. These results provide new insights into the mechanism of CFTR internalization, and may help in the development of new therapies for CFTR correction and lung rehydration in patients with debilitating airway diseases such as COPD.

scholarly journals p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure

2016 ◽  
Vol 310 (6) ◽  
pp. L496-L506 ◽  
Author(s):  
Nivedita Tiwari ◽  
Amarnath S. Marudamuthu ◽  
Yoshikazu Tsukasaki ◽  
Mitsuo Ikebe ◽  
Jian Fu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Cigarette Smoke ◽  
Lung Inflammation ◽  
Cellular Adhesion ◽  
Alveolar Epithelial Cells ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
P53 Expression ◽  
Cellular Adhesion Molecule ◽  
Pai 1

We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.

scholarly journals Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

2010 ◽  
Vol 184 (8) ◽  
pp. 4460-4469 ◽  
Author(s):  
Gregory T. Motz ◽  
Bryan L. Eppert ◽  
Brian W. Wortham ◽  
Robyn M. Amos-Kroohs ◽  
Jennifer L. Flury ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Mouse Model ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Cell Activation ◽  
Nk Cell ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

scholarly journals Total particulate matter concentration skews cigarette smoke's gene expression profile

2016 ◽  
Vol 2 (4) ◽  
pp. 00029-2016 ◽  
Author(s):  
Anna Dvorkin-Gheva ◽  
Gilles Vanderstocken ◽  
Ali Önder Yildirim ◽  
Corry-Anke Brandsma ◽  
Ma'en Obeidat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Particulate Matter ◽  
Cigarette Smoke ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Total Particulate Matter ◽  
Xenobiotic Detoxification

Exposure of small animals to cigarette smoke is widely used as a model to study the pathogenesis of chronic obstructive pulmonary disease. However, protocols and exposure systems utilised vary substantially and it is unclear how these different systems compare.We analysed the gene expression profile of six publically available murine datasets from different cigarette smoke-exposure systems and related the gene signatures to three clinical cohorts.234 genes significantly regulated by cigarette smoke in at least one model were used to construct a 55-gene network containing 17 clusters. Increasing numbers of differentially regulated clusters were associated with higher total particulate matter concentrations in the different datasets. Low total particulate matter-induced genes mainly related to xenobiotic/detoxification responses, while higher total particulate matter activated immune/inflammatory processes in addition to xenobiotic/detoxification responses. To translate these observations to the clinic, we analysed the regulation of the revealed network in three human cohorts. Similar to mice, we observed marked differences in the number of regulated clusters between the cohorts. These differences were not determined by pack-year.Although none of the experimental models exhibited a complete alignment with any of the human cohorts, some exposure systems showed higher resemblance. Thus, depending on the cohort, clinically observed changes in gene expression may be mirrored more closely by specific cigarette smoke exposure systems. This study emphasises the need for careful validation of animal models.

scholarly journals Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Garrett Pehote ◽  
Manish Bodas ◽  
Kathryn Brucia ◽  
Neeraj Vij
Keyword(s):  
Cigarette Smoke ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Cigarette Smoke Extract ◽  
Cigarette Smoke Exposure ◽  
Control Group ◽  
Bacterial Clearance ◽  
Bacterial Killing ◽  
Bactericidal Activities ◽  
Autophagy Inhibition

Introduction. Cigarette smoke (CS) exposure is the leading risk factor for COPD-emphysema pathogenesis. A common characteristic of COPD is impaired phagocytosis that causes frequent exacerbations in patients leading to increased morbidity. However, the underlying mechanism is unclear. Hence, we investigated if CS exposure causes autophagy impairment as a mechanism for diminished bacterial clearance via phagocytosis by utilizing murine macrophages (RAW264.7 cells) and Pseudomonas aeruginosa (PA01-GFP) as an experimental model. Methods. Briefly, RAW cells were treated with cigarette smoke extract (CSE), chloroquine (autophagy inhibitor), TFEB-shRNA, CFTR(inh)-172, and/or fisetin prior to bacterial infection for functional analysis. Results. Bacterial clearance of PA01-GFP was significantly impaired while its survival was promoted by CSE (p<0.01), autophagy inhibition (p<0.05; p<0.01), TFEB knockdown (p<0.01; p<0.001), and inhibition of CFTR function (p<0.001; p<0.01) in comparison to the control group(s) that was significantly recovered by autophagy-inducing antioxidant drug, fisetin, treatment (p<0.05; p<0.01; and p<0.001). Moreover, investigations into other pharmacological properties of fisetin show that it has significant mucolytic and bactericidal activities (p<0.01; p<0.001), which warrants further investigation. Conclusions. Our data suggests that CS-mediated autophagy impairment as a critical mechanism involved in the resulting phagocytic defect, as well as the therapeutic potential of autophagy-inducing drugs in restoring is CS-impaired phagocytosis.

scholarly journals Pneumocystis murina Infection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

2008 ◽  
Vol 76 (8) ◽  
pp. 3481-3490 ◽  
Author(s):  
Paul J. Christensen ◽  
Angela M. Preston ◽  
Tony Ling ◽  
Ming Du ◽  
W. Bradley Fields ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Respiratory Pathogens ◽  
Obstructive Pulmonary Disease ◽  
Immunocompetent Mice

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.

Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C)

2013 ◽  
Vol 125 (10) ◽  
pp. 483-493 ◽  
Author(s):  
Cedric Hubeau ◽  
John E. Kubera ◽  
Katherine Masek-Hammerman ◽  
Cara M. M. Williams
Keyword(s):  
Cigarette Smoke ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Pulmonary Inflammation ◽  
Poly I:C ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chemokine Ligand ◽  
Synthetic Ligand

Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus-like challenges. For this purpose, we used a model where C57BL/6 mice were exposed to CS twice daily via a nose-only system, and concomitant periodic intranasal challenge with poly(I:C), a synthetic ligand for TLR3 (Toll-like receptor 3) that mimics the encounter with double stranded RNA that is carried by influenza-like viruses. This protocol recapitulates several aspects of acute pulmonary inflammation associated with COPD, including prominent airway neutrophilia, insensitivity to steroid treatment and increased levels of several inflammatory cytokines in BAL (bronchoalveolar lavage) samples. Although IL-6-deficient mice exposed to CS/poly(I:C) developed pulmonary inflammation similar to WT (wild-type) controls, WT mice exposed to CS/poly(I:C) and treated intraperitoneally with IL-6-neutralizing antibodies showed significantly lower blood counts of lymphocytes and monocytes, lower BAL levels of IL-6 and CXCL1 (CXC chemokine ligand 1)/KC (keratinocyte chemoattractant), as well as reduced numbers of BAL neutrophils, lymphocytes and macrophages. Our results thus indicate that the systemic neutralization of IL-6 significantly reduces CS/poly(I:C)-induced pulmonary inflammation, which may be a relevant approach to the treatment of episodes of acute pulmonary inflammation associated with COPD.

Liver growth factor treatment reverses emphysema previously established in a cigarette smoke exposure mouse model

2014 ◽  
Vol 307 (9) ◽  
pp. L718-L726 ◽  
Author(s):  
Sandra Pérez-Rial ◽  
Laura del Puerto-Nevado ◽  
Álvaro Girón-Martínez ◽  
Raúl Terrón-Expósito ◽  
Juan J. Díaz-Gil ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cigarette Smoke ◽  
Systemic Inflammation ◽  
Smoke Exposure ◽  
Lung Damage ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Liver Growth ◽  
Tnf Α ◽  
Α Level

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease largely associated with cigarette smoke exposure (CSE) and characterized by pulmonary and extrapulmonary manifestations, including systemic inflammation. Liver growth factor (LGF) is an albumin-bilirubin complex with demonstrated antifibrotic, antioxidant, and antihypertensive actions even at extrahepatic sites. We aimed to determine whether short LGF treatment (1.7 μg/mouse ip; 2 times, 2 wk), once the lung damage was established through the chronic CSE, contributes to improvement of the regeneration of damaged lung tissue, reducing systemic inflammation. We studied AKR/J mice, divided into three groups: control (air-exposed), CSE (chronic CSE), and CSE + LGF (LGF-treated CSE mice). We assessed pulmonary function, morphometric data, and levels of various systemic inflammatory markers to test the LGF regenerative capacity in this system. Our results revealed that the lungs of the CSE animals showed pulmonary emphysema and inflammation, characterized by increased lung compliance, enlargement of alveolar airspaces, systemic inflammation (circulating leukocytes and serum TNF-α level), and in vivo lung matrix metalloproteinase activity. LGF treatment was able to reverse all these parameters, decreasing total cell count in bronchoalveolar lavage fluid and T-lymphocyte infiltration in peripheral blood observed in emphysematous mice and reversing the decrease in monocytes observed in chronic CSE mice, and tends to reduce the neutrophil population and serum TNF-α level. In conclusion, LGF treatment normalizes the physiological and morphological parameters and levels of various systemic inflammatory biomarkers in a chronic CSE AKR/J model, which may have important pathophysiological and therapeutic implications for subjects with stable COPD.

Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition

2006 ◽  
Vol 290 (5) ◽  
pp. L897-L908 ◽  
Author(s):  
John A. Marwick ◽  
Christopher S. Stevenson ◽  
June Giddings ◽  
William MacNee ◽  
Keith Butler ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Vegf Receptor ◽  
Obstructive Pulmonary Disease ◽  
Signaling Complex ◽  
Rat Lungs

VEGF is fundamental in the development and maintenance of the vasculature. VEGF165 signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF165 signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF165-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF165 and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF165-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF165-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.

scholarly journals Curcumin ameliorates chronic obstructive pulmonary disease by modulating autophagy and endoplasmic reticulum stress through regulation of SIRT1 in a rat model

2019 ◽  
Vol 47 (10) ◽  
pp. 4764-4774 ◽  
Author(s):  
Feng Tang ◽  
Chunhua Ling
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protein Expression ◽  
Pulmonary Disease ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
High Dose ◽  
Obstructive Pulmonary Disease ◽  
Gene And Protein Expression

Objectives The ability of curcumin to activate SIRT1 and thereby promote autophagy and inhibit endoplasmic reticulum stress (ERS) in chronic obstructive pulmonary disease (COPD) remains unclear. We investigated the relationship between curcumin and SIRT1 activation in relation to autophagy and ERS in COPD. Methods We developed a rat COPD model by cigarette smoke exposure, and divided the rats into control, COPD, COPD + low-dose curcumin (50 mg/kg), COPD + medium-dose curcumin (100 mg/kg), COPD + high-dose curcumin (150 mg/kg), and COPD + high-dose curcumin + sirtinol (2 mM, 30 μL/kg) groups. Apoptosis was detected by TUNEL assay. SIRT1 gene and protein expression, and protein expression of autophagy-related genes LC3-I, LC3-II, and Beclin1, and ERS-related genes CHOP and GRP78 were measured by reverse transcription-polymerase chain reaction and western blot. Results SIRT1, LC3-I, LC3-II, and Beclin1 expression were significantly decreased and CHOP and GRP78 were enhanced in COPD compared with control rats. Curcumin increased the expression of SIRT1, LC3-I, LC3-II, and Beclin1 and decreased the expression of CHOP and GRP78 in COPD rats. The alleviating effects of curcumin on COPD in the SIRT1-inhibition group were reversed by suppressing LC3-I, LC3-II, and Beclin1 and increasing CHOP and GRP78. Conclusion Curcumin might alleviate COPD by promoting autophagy and inhibiting ERS through SIRT1 activation.

Melatonin protects against COPD by attenuating apoptosis and endoplasmic reticulum stress via upregulating SIRT1 expression in rats

2019 ◽  
Vol 97 (5) ◽  
pp. 386-391 ◽  
Author(s):  
Baimei He ◽  
Wenxuan Zhang ◽  
Jianfeng Qiao ◽  
Zhenyu Peng ◽  
Xiangping Chai
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Er Stress ◽  
Cigarette Smoke ◽  
Alveolar Epithelial Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Sirt1 Expression ◽  
Alveolar Epithelial ◽  
Male Wistar Rats

The apoptosis of bronchial and alveolar epithelial cells plays a key role in chronic obstructive pulmonary disease (COPD). The endoplasmic reticulum (ER) stress induced by cigarette smoke contributes to apoptosis. Previous studies demonstrated that melatonin prevented the development of COPD. In addition, silent information regulator 1 (SIRT1) had a protective effect against COPD. However, it remains unclear whether SIRT1 is involved in the protection of melatonin against COPD. In this study, 32 male Wistar rats were randomly assigned to 4 groups: Control, COPD, COPD + Mel, and COPD + Mel + EX527. Rats were challenged with cigarette smoke and lipopolysaccharide with or without melatonin or EX527 (a selective inhibitor of SIRT1). The lung histopathology, apoptotic index, as well as the protein expressions of cleaved caspase-3, SIRT1, C/EBP homologous protein, and caspase-12 in the lung tissues were measured. These results demonstrated that melatonin attenuated apoptosis and ER stress in the lung tissues of rats with COPD. In addition, melatonin increased SIRT1 expression in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 upregulated ER stress and abolished the protective effect of melatonin against apoptosis. In conclusion, these findings suggested that melatonin protected against COPD by attenuating apoptosis and ER stress via upregulating SIRT1 expression in rats.

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