Persistence of pulmonary tertiary lymphoid tissues and anti-nuclear antibodies following cessation of cigarette smoke exposure.
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ABSTRACT:
SUBMITTER: Morissette MC
PROVIDER: S-EPMC4021094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cigarette smoke (CS) predisposes exposed individuals to respiratory infections not only by suppressing immune response but also by enhancing the virulence of pathogenic bacteria. As per our observations, in methicillin-resistant Staphylococcus aureus strain USA300, CS extract (CSE) potentiates biofilm formation via the down-regulation of quorum-sensing regulon accessory gene regulator. Because accessory gene regulator is a global regulator of the staphylococcal virulome, in the present study we sought to identify the effects of CS exposure on staphylococcal gene expression using RNAseq. Comparative analysis of RNAseq profiles revealed the up-regulation of important virulence genes encoding surface adhesins (fibronectin- and fibrinogen-binding proteins A and B and clumping factor B) and proteins involved in immune evasion, such as staphylocoagulase, staphylococcal protein A, and nuclease. In concurrence with the RNAseq data, we observed: (1) significant up-regulation of the ability of CSE-exposed USA300 to evade phagocytosis by macrophages and neutrophils, a known function of staphylococcal protein A; and (2) twofold higher (P < 0.001) number of CSE-exposed USA300 escaping neutrophil extracellular trap-mediated killing by neutrophils as a result of CS-mediated induction of nuclease. Importantly, in three different mouse strains, C57BL6/J, Balb/C, and A/J, we observed significantly higher pulmonary bacterial burden in animals infected with CSE-exposed USA300 as compared with medium-exposed control USA300. Taken together, these observations indicate that bioactive chemicals in CS induce hypervirulence by augmenting the ability of USA300 to evade bactericidal functions of leukocytes, such as phagocytosis and neutrophil extracellular trap-mediated killing.
| S-EPMC5070110 | biostudies-literature
Project description:Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf-expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease.
| S-EPMC7175375 | biostudies-literature
Project description:Although smoking cessation shows clear cardiovascular risk benefits, lung-related disease risk remains higher in former smokers than in never smokers. To better understand the factors involved in this phenomenon, ApoE-/- mice were exposed to mainstream cigarette smoke (CS) or a smoking cessation-mimicking protocol for up to six months. Analysis of bronchoalveolar lavage fluid (BALF) from CS-exposed ApoE-/- mice revealed the presence of high concentrations of mediators involved in functions ranging from inflammation to cell proliferation and tissue remodeling. Gene expression levels for many analytes found elevated in BALF were also increased in lung tissue, indicating that the inflammatory response was the result of local tissue activation and the contribution of recruited inflammatory cells. Gene set enrichment analysis (GSEA) of expression data from lungs of CS-exposed mice showed activation of pathways involved in cell proliferation and tissue remodeling and a progressive deactivation upon smoke exposure cessation. Distinct activation patterns of inflammation, complement, and xenobiotic metabolism pathways were found in nasal epithelium and lung parenchyma during CS exposure and smoking cessation. Exposure of ApoE-/- mice to CS for up to 6 months induced adaptive and inflammatory responses in the respiratory tract that were partially deactivated upon cessation. We were able to reveal molecular perturbations accompanying these changes during CS exposure and cessation. Differential CS-mediated responses of pulmonary and nasal tissues reflect common mechanisms but also the varying degrees of epithelial functional specialization along the respiratory tract. These findings provide novel clues for the identification of markers of COPD progression.
2013-10-19 | E-MTAB-1390 | biostudies-arrayexpress
Project description:IntroductionThe role inflammasomes play in chronic obstructive pulmonary disease (COPD) is unclear. We hypothesised that the AIM2 inflammasome is activated in the airways of COPD patients, and in response to cigarette smoke.MethodsLung tissue, bronchoscopy-derived alveolar macrophages and bronchial epithelial cells from COPD patients and healthy donors; lungs from cigarette smoke-exposed mice; and cigarette smoke extract-stimulated alveolar macrophages from healthy controls and HBEC30KT cell line were investigated. AIM2 inflammasome activation was assessed by multi-fluorescence quantitative confocal microscopy of speck foci positive for AIM2, inflammasome component ASC and cleaved IL-1β. Subcellular AIM2 localization was assessed by confocal microscopy, and immunoblot of fractionated cell lysates. Nuclear localization was supported by in-silico analysis of nuclear localization predicted scores of peptide sequences. Nuclear and cytoplasmic AIM2 was demonstrated by immunoblot in both cellular fractions from HBEC30KT cells.ResultsIncreased cytoplasmic AIM2 speck foci, colocalized with cleaved IL-1β, were demonstrated in COPD lungs (n = 9) vs. control (n = 5), showing significant positive correlations with GOLD stages. AIM2 nuclear-to-cytoplasmic redistribution was demonstrated in bronchiolar epithelium in cigarette-exposed mice and in HBEC30KT cells post 24 h stimulation with 5% cigarette smoke extract. Alveolar macrophages from 8 healthy non-smokers responded to cigarette smoke extract with an > 8-fold increase (p < 0.05) of cytoplasmic AIM2 and > 6-fold increase (p < 0.01) of colocalized cleaved IL-1β speck foci, which were also localized with ASC.ConclusionThe AIM2 inflammasome is activated in the airway of COPD patients, and in response to cigarette smoke exposure, associated with a nuclear to cytoplasmic shift in the distribution of AIM2.
| S-EPMC8141226 | biostudies-literature
Project description:Modern 'omic' technologies, where changes in the expression of thousands of molecular species can be investigated in even a simple experiment, provide contemporary biomedical researchers with an unprecedented level of molecular granularity. An outstanding challenge is transformation of this experimental detail and complexity into meaningful biological insight. This is especially true for drug development and toxicological risk assessment, where molecular profiling data is increasingly being used to investigate the biological effects of a variety of exposures, from drugs to environmental factors, on human systems. Recently, we proposed a systems-based strategy for objectively predicting the mechanistic impact of biologically active substances from transcriptomic data, and report here on an initial implementation of this strategy. We applied a set of biological network models and novel scoring algorithms to investigate transcriptomic data from a range of experimental systems. Importantly, this approach enabled continuity between investigation at the molecular, pathway, and systems levels. For both in vitro systems with simple exposures and in vivo systems with complex exposures, the method was able to identify and provide relative quantitation for the precise mechanisms that were impacted. For example, when applied to data from mice exposed to cigarette smoke, the methodology correctly identified known mechanistic effects of the exposure, including increased pulmonary inflammation, necrosis, and proliferation. Importantly, many of the effects indicated by the methodology were supported by experimental endpoint data, providing further objective validation of the general approach. We propose that various fields of human disease research, from drug development to consumer product testing, could benefit from using this or similar approaches to evaluate the biological impact of exposures.
2013-02-15 | E-MTAB-1313 | biostudies-arrayexpress
Project description:IL-17 is critical in lung lymphoid neogenesis in COPD, but the cellular and molecular mechanisms remain to be elucidated. Receptor activator of nuclear factor-κB ligand (RANKL) functions in lymphoid follicle formation in other organs, whether it is involved in IL-17A-dependent lymphoid neogenesis in COPD is unknown. To elucidate the expression and functional role of IL-17A/RANKL pathway in COPD. We first quantified and localized RANKL, its receptor RANK and IL-17A in lungs of patients with COPD, smokers and non-smokers. Next, IL-17A-/- and wild-type (WT) mice were exposed to air or cigarette smoke (CS) for 24 weeks, and lung lymphoid follicles and RANKL-RANK expression were measured. Lastly, we studied the in vitro biological function of RANKL pertaining to lymphoid neogenesis. We found that the expressions of RANKL-RANK and IL-17A, together with lymphoid follicles, were increased in lung tissues from patients with COPD. In WT mice exposed to CS, RANKL-RANK expressions were prominent in lung lymphoid follicles, which were absent in IL-17A-/- mice exposed to CS. In the lymphoid follicles, RANKL+ cells were identified mostly as B cells and RANK was localized in dendritic cells (DCs). In vitro IL-17A increased the expressions of RANKL in B cells and RANK in DCs, which in turn responded to RANKL stimulation by upregulation of CXCL13. Altogether, these results suggest that B lymphocyte RANKL pathway is involved in IL-17A-dependent lymphoid neogenesis in COPD.
| S-EPMC7892459 | biostudies-literature
Project description:Cigarette smoke (CS) exposure increases the risk for acute respiratory distress syndrome in humans and promotes alveolar-capillary barrier permeability and acute lung injury in animal models. However, the underlying mechanisms are not well understood. Mitochondrial fusion and fission are essential for mitochondrial homeostasis in health and disease. In this study, we hypothesized that CS caused endothelial injury via an imbalance of mitochondrial fusion and fission and resultant mitochondrial oxidative stress and dysfunction. We noted that CS altered mitochondrial morphology by shortening mitochondrial networks and causing perinuclear accumulation of damaged mitochondria in primary rat lung microvascular endothelial cells. We also found that CS increased mitochondrial fission likely by decreasing Drp1-S637 and increasing FIS1, Drp1-S616 phosphorylation, mitochondrial translocation, and tetramerization and reduced mitochondrial fusion likely by decreasing Mfn2 in lung microvascular endothelial cells and mouse lungs. CS also caused aberrant mitophagy, increased mitochondrial oxidative stress, and reduced mitochondrial respiration. An inhibitor of mitochondrial fission and a mitochondria-specific antioxidant prevented CS-induced increased endothelial barrier dysfunction and apoptosis. Our data suggest that excessive mitochondrial fission and resultant oxidative stress are essential mediators of CS-induced endothelial injury and that inhibition of mitochondrial fission and mitochondria-specific antioxidants may be useful therapeutic strategies for CS-induced endothelial injury and associated pulmonary diseases.
| S-EPMC7605166 | biostudies-literature
Project description:Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor+ (p75NTR+) fibroblasts and homeostatic chemokine-producing fibroblasts inside TLTs, and retinoic acid-producing fibroblasts around TLTs. Deletion of CD4+ cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.
| S-EPMC5033938 | biostudies-literature
Project description:Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1β, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma.
| S-EPMC9253141 | biostudies-literature
Project description:BackgroundPhysiological rhythms in mammals are essential for maintaining health, whereas disruptions may cause or exacerbate disease pathogenesis. As such, our objective was to characterize how cigarette smoke exposure affects physiological rhythms of otherwise healthy mice using telemetry and cosinor analysis.MethodsFemale BALB/c mice were implanted with telemetry devices to measure body temperature, heart rate, systolic blood pressure (SBP), and activity. Following baseline measurements, mice were exposed to cigarette smoke for approximately 50 min twice daily during weekdays over 24 weeks. Physiological parameters were recorded after 1, 4, 8, and 24 weeks of exposure or after 4 weeks cessation following 4 weeks of cigarette smoke exposure.ResultsAcute cigarette smoke exposure resulted in anapyrexia, and bradycardia, with divergent effects on SBP. Long term, cigarette smoke exposure disrupted physiological rhythms after just 1 week, which persisted across 24 weeks of exposure (as shown by mixed effects on mesor, amplitude, acrophase, and goodness-of-fit using cosinor analysis). Four weeks of cessation was insufficient to allow full recovery of rhythms.ConclusionOur characterization of the pathophysiology of cigarette smoke exposure on physiological rhythms of mice suggests that rhythm disruption may precede and contribute to disease pathogenesis. These findings provide a clear rationale and guide for the future use of chronotherapeutics.
| S-EPMC7609783 | biostudies-literature