Innate Immune Processes Are Sufficient for Driving Cigarette Smoke–Induced Inflammation in Mice

Botelho, Fernando Mendes; Gaschler, Gordon J.; Kianpour, Sussan; Zavitz, Cale C. J.; Trimble, Nancy J.; Nikota, Jake K.; Bauer, Carla M. T.; Stämpfli, Martin R.

doi:10.1165/rcmb.2008-0301oc

Cited by 96 publications

(136 citation statements)

References 39 publications

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“…In contrast to the data presented in this study and the observations of others (16,35,36), there is some data suggesting that NK cells may be functionally suppressed in COPD. However, the interpretation of these reports is limited by small samples sizes, the use of non-COPD smokers with unknown patient characteristics, or in vitro treatment of PBMCs with Cs extract (55,56).…”

Section: Discussioncontrasting

confidence: 99%

“…Additional evidence implicating NK cells in the development of COPD comes from studies on immunocompromised mice exposed to CS (35,36). It has been demonstrated that, in the absence of T cells and B cells, the development of COPD phenotypes still occurred following chronic CS exposure (35,36). In addition, we have recently demonstrated a role for the innate functions of cytotoxic lymphocytes in the pathogenesis of COPD (6).…”

Section: Discussionmentioning

confidence: 95%

“…However, the in vivo relevance of NK cell priming is a limitation of this work and requires further study. Additional evidence implicating NK cells in the development of COPD comes from studies on immunocompromised mice exposed to CS (35,36). It has been demonstrated that, in the absence of T cells and B cells, the development of COPD phenotypes still occurred following chronic CS exposure (35,36).…”

Section: Discussionmentioning

confidence: 99%

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

Motz¹,

Eppert²,

Wortham³

et al. 2010

The Journal of Immunology

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Chronic obstructive pulmonary disease (COPD) is a debilitating, progressive lung disease punctuated by exacerbations of symptoms. COPD exacerbations are most often associated with viral infections, and exposure to cigarette smoke (CS) followed by viral infection has been shown experimentally to enhance lung inflammation, tissue destruction, and airway fibrosis. Despite this, however, the cellular mechanisms responsible for this effect are unknown. In this study, we examined NK cell function in a mouse model of COPD given the vital role of NK cells following viral infection. Ex vivo stimulation of lung leukocytes with poly(I:C), ssRNA40, or ODN1826 enhanced production of NK cell-derived IFN-γ in CS-exposed mice. NK cells from CS-exposed mice exhibited a novel form of priming; highly purified NK cells from CS-exposed mice, relative to NK cells from filtered air-exposed mice, produced more IFN-γ following stimulation with IL-12, IL-18, or both. Further, NK cell priming was lost following smoking cessation. NKG2D stimulation through overexpression of Raet1 on the lung epithelium primed NK cell responsiveness to poly(I:C), ssRNA40, or ODN1826 stimulation, but not cytokine stimulation. In addition, NK cells from CS-exposed mice expressed more cell surface CD107a upon stimulation, demonstrating that the NK cell degranulation response was also primed. Together, these results reveal a novel mechanism of activation of the innate immune system and highlight NK cells as important cellular targets in controlling COPD exacerbations.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

Motz¹,

Eppert²,

Wortham³

et al. 2010

The Journal of Immunology

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“…Details of the exposure protocol were reported previously (17). Average total particulate matter during exposure was 786 mg/L.…”

Section: Cs Exposure Protocolmentioning

confidence: 99%

Detection of Lung Dysfunction Using Ventilation and Perfusion SPECT in a Mouse Model of Chronic Cigarette Smoke Exposure

et al. 2013

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Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide. Exposure to cigarette smoke (CS) is a major risk factor for developing this chronic airflow impairment, but the early progression of disease is not well defined or understood. Ventilation/perfusion (V/Q) SPECT provides a noninvasive assessment of lung function to further our current understanding of how CS affects the lung. Methods: BALB/c mice were imaged with V/Q SPECT and CT after 8 and 24 wk of whole-body exposure to mainstream CS. Bronchoalveolar lavage was collected and cell differentials produced to determine inflammatory patterns. Histologic lung sections were collected, and a semiautomated quantitative analysis of airspace enlargement was applied to whole histology slices. Results: Exposure to CS induced an inflammatory response that included increases in the numbers of both mononuclear cells and neutrophils. Airspace enlargement was also significantly increased at 8 wk of CS exposure and was still more pronounced at 24 wk. Ventilation and perfusion correlation at the voxel level depicted a significant decrease in matching at 8 wk of CS exposure that was also apparent after 24 wk. The standard deviation (SD) of the log(V/Q) curve, a basic measure of heterogeneity, was increased from 0.44 6 0.02 in age-matched controls to 0.62 6 0.05 with CS exposure at 24 wk, indicating an increase in V/Q mismatching between 8 and 24 wk of CS exposure. CT, however, was not capable of discriminating control from CS-exposed animals at either time point, even with greater resolution and respiratory gating. Conclusion: This study demonstrated that, before CT detection of structural changes, V/Q imaging detected changes in gas-exchange potential. This functional impairment corresponded to increased lung inflammation and increased airspace enlargement. In vivo V/Q imaging can detect early changes to the lung caused by CS exposure and thus provides a noninvasive method of longitudinally studying lung dysfunction in preclinical models. In the future, these measures could be applied clinically to study and diagnose the early stages of chronic obstructive pulmonary disease.

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“…2008; Botelho et al. 2010). We previously reported elevated levels of autoantibodies following 24 weeks of smoke exposure that persisted following smoking cessation, and coincided with the formation of TLT in the lungs (Morissette et al.…”

Section: Discussionmentioning

confidence: 99%

Role of BAFF in pulmonary autoantibody responses induced by chronic cigarette smoke exposure in mice

Morissette

Gao

Shen

et al. 2016

Physiological Reports

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Emerging evidence suggests that autoimmune processes are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). In this study, we assessed the expression of B‐cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke‐induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. We observed that BAFF levels were elevated in smokers and mice exposed to cigarette smoke. In mice, BAFF expression was rapidly induced in the lungs following 4 days of cigarette smoke exposure and remained elevated following 8 and 24 weeks of exposure. Alveolar macrophages were the major source of BAFF. Blockade of BAFF using a BAFF receptor‐Fc (BAFFR‐Fc) construct prevented pulmonary ANA and TLT formation when delivered concurrent with cigarette smoke exposure. Under these conditions, no impact on lung inflammation was observed. However, administration of BAFFR‐Fc following smoking cessation markedly reduced the number of TLTs and ANA levels and, of note, reduced pulmonary neutrophilia. Altogether, this study shows for the first time a central role of BAFF in the induction and maintenance of cigarette smoke‐induced pulmonary ANA and suggests that BAFF blockade following smoking cessation could have beneficial effects on persistent inflammatory processes.In this study, we assessed the expression of B‐cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke‐induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. Data presented show that BAFF plays a central role in the induction and maintenance of cigarette smoke‐induced pulmonary ANA and suggest a therapeutic potential for BAFF blockade in limiting autoimmune processes associated with smoking.

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Innate Immune Processes Are Sufficient for Driving Cigarette Smoke–Induced Inflammation in Mice

Cited by 96 publications

References 39 publications

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

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

Detection of Lung Dysfunction Using Ventilation and Perfusion SPECT in a Mouse Model of Chronic Cigarette Smoke Exposure

Role of BAFF in pulmonary autoantibody responses induced by chronic cigarette smoke exposure in mice

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