Losartan does not inhibit cigarette smoke-induced lung inflammation in mice.
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ABSTRACT:
SUBMITTER: Hepworth ML
PROVIDER: S-EPMC6803700 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
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Project description:The aim was to determine whether losartan reduces cigarette smoke (CS)-induced airway inflammation and mucus hypersecretion in an in vitro model and a small clinical trial. Primary human bronchial epithelial cells (HBECs) were differentiated at the air-liquid interface (ALI) and exposed to CS. Expression of transforming growth factor (TGF)-β1 and the mucin MUC5AC, and expression or activity of matrix metalloproteinase (MMP)-9 were measured after CS exposure. Parameters of mucociliary clearance were evaluated by measuring airway surface liquid volumes, mucus concentrations, and conductance of cystic fibrosis transmembrane conductance regulator (CFTR) and large conductance, Ca2+-activated and voltage-dependent potassium (BK) channels. Nasal cells were collected from study participants and expression of MUC5AC, TGF-β1, and MMP-9 mRNAs was measured before and after losartan treatment. In vitro, CS exposure of HBECs caused a significant increase in mRNA expression of MUC5AC and TGF-β1 and MMP-9 activity and decreased CFTR and BK channel activities, thereby reducing airway surface liquid volumes and increasing mucus concentrations. Treatment of HBECs with losartan rescued CS-induced CFTR and BK dysfunction and caused a significant decrease in MUC5AC expression and mucus concentrations, partially by inhibiting TGF-β signalling. In a prospective clinical study, cigarette smokers showed significantly reduced mRNA expression levels of MUC5AC, TGF-β1, and MMP-9 in the upper airways after 2 months of losartan treatment. Our findings suggest that losartan may be an effective therapy to reduce inflammation and mucus hypersecretion in CS-induced chronic airway diseases.
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Project description:Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, ?7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine.
| S-EPMC3897646 | biostudies-literature
Project description:Influenza A virus (IAV) infections are a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Oxidative stress is increased in COPD, IAV-induced lung inflammation and AECOPD. Therefore, we investigated whether targeting oxidative stress with the Nox2 oxidase inhibitors and ROS scavengers, apocynin and ebselen could ameliorate lung inflammation in a mouse model of AECOPD. Male BALB/c mice were exposed to cigarette smoke (CS) generated from 9 cigarettes per day for 4 days. On day 5, mice were infected with 1 × 10(4.5) PFUs of the IAV Mem71 (H3N1). BALF inflammation, viral titers, superoxide production and whole lung cytokine, chemokine and protease mRNA expression were assessed 3 and 7 days post infection. IAV infection resulted in a greater increase in BALF inflammation in mice that had been exposed to CS compared to non-smoking mice. This increase in BALF inflammation in CS-exposed mice caused by IAV infection was associated with elevated gene expression of pro-inflammatory cytokines, chemokines and proteases, compared to CS alone mice. Apocynin and ebselen significantly reduced the exacerbated BALF inflammation and pro-inflammatory cytokine, chemokine and protease expression caused by IAV infection in CS mice. Targeting oxidative stress using apocynin and ebselen reduces IAV-induced lung inflammation in CS-exposed mice and may be therapeutically exploited to alleviate AECOPD.
| S-EPMC4753462 | biostudies-literature
Project description:Viral infections trigger exacerbations in chronic obstructive pulmonary disease (COPD), and tiotropium, a M3 receptor antagonist, reduces exacerbations in patients by unknown mechanisms. In this report, we investigated whether tiotropium has anti-inflammatory effects in mice exposed to cigarette smoke (CS) and infected with influenza virus A/PR/8/34 (H1N1) or respiratory syncytial virus (RSV) and compared these effects with those of steroid fluticasone and PDE4-inhibitor roflumilast. Mice were exposed to CS; infected with H1N1 or RSV; and treated with tiotropium, fluticasone, or roflumilast. The amount of cells and cytokine levels in the airways, lung function, and viral load was determined. NCI-H292 cells were infected with H1N1 or RSV and treated with the drugs. In CS/H1N1-exposed mice, tiotropium reduced neutrophil and macrophage numbers and levels of interleukin-6 (IL-6) and interferon-? (IFN-?) in the airways and improved lung function. In contrast, fluticasone increased the loss of body weight; failed to reduce neutrophil or macrophage numbers; increased IL-6, KC, and tumor necrosis factor-? (TNF-?) in the lungs; and worsened lung function. Treatment with roflumilast reduced macrophage numbers, IL-6, and KC in the lungs but had no effect on neutrophil numbers or lung function. In CS/RSV-exposed mice, treatment with tiotropium, but not fluticasone or roflumilast, reduced neutrophil numbers and IL-6 and TNF-? levels in the lungs. Viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after fluticasone treatment, whereas tiotropium and roflumilast had no effect. In conclusion, tiotropium has anti-inflammatory effects on CS/virus-induced inflammation in mice that are superior to the effects of roflumilast and fluticasone. This finding might help to explain the observed reduction of exacerbation rates in COPD patients.
| S-EPMC4885512 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-? signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-? signaling would protect against CS-induced lung injury. We first confirmed that TGF-? signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-? signaling in CS-exposed mice. Systemic administration of a TGF-?-specific neutralizing antibody normalized TGF-? signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-? signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-? signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-?-targeted therapies for patients with COPD.
| S-EPMC3248282 | biostudies-literature
Project description:IntroductionCigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar-epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice.MethodsAdult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA.ResultsIn CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T-cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability.ConclusionsThese results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury.ImplicationsOur results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for evaluating the acute pulmonary toxicity of existing and/or novel tobacco products and identifying biomarkers of tobacco-related lung injury.
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Project description:Chronic obstructive pulmonary disease (COPD) and lung cancer represent two diseases that share a strong risk factor in smoking, and COPD increases risk of lung cancer even after adjusting for the effects of smoking. These diseases not only occur jointly within an individual but also there is evidence of shared occurrence within families. Understanding the genetic contributions to these diseases, both individually and jointly, is needed to identify the highest risk group for screening and targeted prevention, as well as aiding in the development of targeted treatments. The chromosomal regions that have been identified as being associated either jointly or independently with lung cancer, COPD, nicotine addiction, and lung function are presented. Studies jointly measuring genetic variation in lung cancer and COPD have been limited by the lack of detailed COPD diagnosis and severity data in lung cancer populations, the lack of lung cancer-specific phenotypes (histology and tumor markers) in COPD populations, and the lack of inclusion of minorities. African Americans, who smoke fewer cigarettes per day and have different linkage disequilibrium and disease patterns than whites, and Asians, also with different patterns of exposure to lung carcinogens and linkage patterns, will provide invaluable information to better understand shared and independent genetic contributions to lung cancer and COPD to more fully define the highest risk group of individuals who will most benefit from screening and to develop molecular signatures to aid in targeted treatment and prevention efforts.
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Project description:Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.
| S-EPMC6305334 | biostudies-literature
Project description:Exposure to cigarette smoke (CS) is the primary factor associated with the development of chronic obstructive pulmonary disease (COPD). CS increases the level of oxidants in the lungs, resulting in a depletion of antioxidants, which promotes oxidative stress and the destruction of alveolar tissue. In response to CS, pulmonary epithelial cells counteract increased levels of oxidants by activating Nrf2-dependent pathways to augment the expression of detoxification and antioxidant enzymes, thereby protecting the lung from injury. We hypothesize that increasing the pathways activated by Nrf2 will afford protection against CS-induced lung damage. To this end we have developed a novel mouse model in which the cytosolic inhibitor of Nrf2, Keap1, is genetically deleted in Clara cells, which predominate in the upper airways in mice. Deletion of Keap1 in Clara cells resulted in increased expression of Nrf2-dependent genes, such as Nqo1 and Gclm, as determined by microarray analysis and quantitative PCR. Deletion of Keap1 in airway epithelium decreased Keap1 protein levels and significantly increased the total level of glutathione in the lungs. Increased Nrf2 activation protected Clara cells against oxidative stress ex vivo and attenuated oxidative stress and CS-induced inflammation in vivo. Expression of KEAP1 was also decreased in human epithelial cells through siRNA transfection, which increased the expression of Nrf2-dependent genes and attenuated oxidative stress. In conclusion, activating Nrf2 pathways in tissue-specific Keap1 knockout mice represents an important genetic approach against oxidant-induced lung damage.
| S-EPMC2874439 | biostudies-literature
Project description:Cigarette smoke (CS)-exposed mice have been used to model airway inflammation and emphesema in humans; however, the impact of exposure duration, sex, and strain differences in susceptibility to progression of airway inflammation and to emphesema are poorly investigated. This study was designed to determine the association between inflammation and emphysema by exposing 2 strains of mice, C3H/HeN (C3H) and C57BL/6 (Bl/6), to filtered air (FA) or CS for 10, 16, or 22 weeks. Both genders and strains of CS-exposed mice developed pulmonary inflammation as characterized by cell counts in the bronchoalveolar lavage fluid (BALF) and the levels of matrix metalloproteinases (MMPs) in the BALF. CS exposure caused persistently higher number of BALF macrophages in C3H compared to BL/6 mice, while more BALF neutrophils and persistently higher MMP-2 and MMP-9 levels were observed in BL/6 mice. The mean linear intercept (Lm) increased progressively by 26%, 33%, and 55% at 10, 16, and 22 weeks, respectively, in CS-exposed C3H mice compared to the matched air controls. In BL/6 mice, although CS exposure also increased the Lm compared to FA controls, no further increase in Lm beyond the levels observed at 16 weeks of exposure was observed by 22 weeks. These findings suggest that extent of inflammation is not associated with severity of emphysema and underscores the importance of carefully selecting the mouse strains and endpoints when exploring effective treatments for emphesema.
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