Cigarette Smoke Exposure as a Model of Inflammation Associated with COPD

Eltom, Suffwan; Stevenson, Christopher S.; Birrell, Mark A.

doi:10.1002/0471141755.ph0564s60

Cited by 17 publications

(8 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reason for the discrepancy between data sets is not known but our data is in line with a previous finding that LPS challenge did not increase caspase 1 activity (a downstream marker of P2X 7 receptor activation) [39]. Furthermore, we have detected an increase in BALF ATP levels in a smoke driven model [53], but no similar increase after LPS challenge (data not shown).…”

Section: Discussionsupporting

confidence: 84%

TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung

et al. 2014

Self Cite

View full text Add to dashboard Cite

BackgroundThe IL-1 family of cytokines is known to play an important role in inflammation therefore understanding the mechanism by which they are produced is paramount. Despite the recent plethora of publications dedicated to the study of these cytokines, the mechanism by which they are produced in the airway following endotoxin, Lipopolysaccharide (LPS), exposure is currently unclear. The aim was to determine the mechanism by which the IL-1 cytokines are produced after LPS inhaled challenge.MethodsMice were challenged with aerosolised LPS, and lung tissue and bronchiolar lavage fluid (BALF) collected. Targets were measured at the mRNA and protein level; caspase activity was determined using specific assays.ResultsBALF IL-1b/IL-18, but not IL-1a, was dependent on Ice Protease-Activating Factor (IPAF), and to a lesser extent Apoptosis-associated Speck-like protein containing a CARD (ASC). Interestingly, although we measured an increase in mRNA expression for caspase 1 and 11, we could not detect an increase in lung enzyme activity or a role for them in IL-1a/b production. Further investigations showed that whilst we could detect an increase in caspase 8 activity at later points in the time course (during resolution of inflammation), it appeared to play no role in the production of IL-1 cytokines in this model system.ConclusionsTLR4 activation increases levels of BALF IL-1b/IL-18 via an IPAF dependent and caspase 1/11/8 independent pathway. Furthermore, it would appear that the presence of IL-1a in the BALF is independent of these pathways. This novel data sheds light on innate signalling pathways in the lung that control the production of these key inflammatory cytokines.

show abstract

Section: Discussionsupporting

confidence: 84%

TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…In these studies we could detect an increase in BALF ATP and KC levels after CS challenge but the mechanisms involved are not known [7] , [8] . However, what is clear from these studies is that both these mediators are not controlled by the signalling downstream of the P2X 7 receptor and are independent of neutrophilia.…”

Section: Discussionmentioning

confidence: 89%

“…Recently there has been growing evidence to implicate the ATP-P2X 7 -inflammasome-caspase 1-IL-1/18 axis in murine models of smoke induced airway inflammation, healthy smokers and in patients suffering from COPD. ATP levels have been reported to be increased in the lungs of smoke driven models and COPD patients [5] – [7] . Activation of the P2X 7 receptor has been shown to be central to smoke induced airway inflammation [8] , [9] .…”

Section: Introductionmentioning

confidence: 99%

Role of the Inflammasome-Caspase1/11-IL-1/18 Axis in Cigarette Smoke Driven Airway Inflammation: An Insight into the Pathogenesis of COPD

et al. 2014

Self Cite

View full text Add to dashboard Cite

BackgroundChronic Obstructive Pulmonary Disease (COPD) is an inflammatory airway disease often associated with cigarette smoke (CS) exposure. The disease is increasing in global prevalence and there is no effective therapy. A major step forward would be to understand the disease pathogenesis. The ATP-P2X7 pathway plays a dominant role in murine models of CS induced airway inflammation, and markers of activation of this axis are upregulated in patients with COPD. This strongly suggests that the axis could be important in the pathogenesis of COPD. The aim of this study was to perform a detailed characterisation of the signalling pathway components involved in the CS-driven, P2X7 dependent airway inflammation.MethodsWe used a murine model system, bioassays and a range of genetically modified mice to better understand this complex signalling pathway.ResultsThe inflammasome-associated proteins NALP3 and ASC, but not IPAF and AIM2, are required for CS-induced IL-1β/IL-18 release, but not IL-1α. This was associated with a partial decrease in lung tissue caspase 1 activity and BALF neutrophilia. Mice missing caspase 1/11 or caspase 11 had markedly attenuated levels of all three cytokines and neutrophilia. Finally the mechanism by which these inflammatory proteins are involved in the CS-induced neutrophilia appeared to be via the induction of proteins involved in neutrophil transmigration e.g. E-Selectin.ConclusionThis data indicates a key role for the P2X7-NALP3/ASC-caspase1/11-IL-1β/IL-18 axis in CS induced airway inflammation, highlighting this pathway as a possible therapeutic target for the treatment of COPD.

show abstract

“…E3). Recently, smoking-induced COPD models have been in the focus of respiratory research (Eltom et al, 2013;Luo et al, 2017;Wang et al, 2014), but none of these studies investigated the effects of chronic cigarette smoking on cardiac alterations. Although Wang et al investigated the alterations of the right ventricle in a rat model of smoking-induced COPD, they did not determine either cardiac functional parameters or MMPs activity and inflammatory cytokines, but only right ventricular hypertrophy index (Wang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Integrative characterization of chronic cigarette smoke-induced cardiopulmonary comorbidities in a mouse model

Kemény

Csekő

Szitter

et al. 2017

Environmental Pollution

View full text Add to dashboard Cite

Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model. Some respiratory alterations characteristic of emphysema (decreased airway resistance: Rl; end-expiratory work and pause: EEW, EEP; expiration time: Te; increased tidal mid-expiratory flow: EF50) were detected in anaesthetized C57BL/6 mice, unrestrained plethysmography did not show changes. Typical histopathological signs were peribronchial/perivascular (PB/PV) edema at month 1, neutrophil/macrophage infiltration at month 2, interstitial leukocyte accumulation at months 3-4, and emphysema/atelectasis at months 5-6 quantified by mean linear intercept measurement. Emphysema was proven by micro-CT quantification. Leukocyte number in the bronchoalveolar lavage at month 2 and lung matrix metalloproteinases-2 and 9 (MMP-2/MMP-9) activities in months 5-6 significantly increased. Smoking triggered complex cytokine profile change in the lung with one characteristic inflammatory peak of C5a, interleukin-1α and its receptor antagonist (IL-1α, IL-1ra), monokine induced by gamma interferon (MIG), macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) at months 2-3, and another peak of interferon-γ (IFN-γ), IL-4, 7, 13, 17, 27 related to tissue destruction. Transient systolic and diastolic ventricular dysfunction developed after 1-2 months shown by significantly decreased ejection fraction (EF%) and deceleration time, respectively. These parameters together with the tricuspid annular plane systolic excursion (TAPSE) decreased again after 5-6 months. Soluble intercellular adhesion molecule-1 (sICAM-1) significantly increased in the heart homogenates at month 6, while other inflammatory cytokines were undetectable. This is the first study demonstrating smoking duration-dependent, complex cardiopulmonary alterations characteristic to COPD, in which inflammatory cytokine cascades and MMP-2/9 might be responsible for pulmonary destruction and sICAM-1 for heart dysfunction.

show abstract

Cigarette Smoke Exposure as a Model of Inflammation Associated with COPD

Cited by 17 publications

References 29 publications

TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung

TLR4 activation induces IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung

Role of the Inflammasome-Caspase1/11-IL-1/18 Axis in Cigarette Smoke Driven Airway Inflammation: An Insight into the Pathogenesis of COPD

Integrative characterization of chronic cigarette smoke-induced cardiopulmonary comorbidities in a mouse model

Contact Info

Product

Resources

About