Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness

McGovern, Toby K.; Chen, Michael; Allard, Benoît; Larsson, K; Martin, James G.; Adner, Mikael

doi:10.1152/ajplung.00172.2015

Cited by 25 publications

(25 citation statements)

References 47 publications

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“…Firstly, DARC is unlikely to affect asthma severity through effects on airway inflammation or immune phenotype. Indeed, the effect on neutrophils was rather small and conflicts with previous findings suggesting that neutrophils promote AHR . Although recent in vitro findings suggest that loss of DARC promotes CXCL1‐induced ASM proliferation, we did not detect an effect of DARC on α ‐smooth muscle actin mRNA or any other markers of airway remodelling.…”

Section: Discussioncontrasting

confidence: 99%

“…Indeed, the effect on neutrophils was rather small and conflicts with previous findings suggesting that neutrophils promote AHR. 28,29 Although recent in vitro findings suggest that loss of DARC promotes CXCL1-induced ASM proliferation, 7 we did not detect an effect of DARC on a-smooth muscle actin mRNA or any other markers of airway remodelling. Although we cannot rule out that the relatively short exposure period (3 weeks) may be insufficient to detect an effect of DARC on airway remodelling, we were able to detect an effect of AHR at this time-point.…”

Section: Darc Snps Are Associated With Symptoms and Healthcare Utilcontrasting

confidence: 74%

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The Duffy antigen receptor for chemokines regulates asthma pathophysiology

Chapman

Mougey

Velden

et al. 2017

Clin Experimental Allergy

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Background The Duffy Antigen Receptor for Chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. Objective To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. Methods Mice with targeted disruption of the Darc gene (DarcΔE2) or WT mice were challenged over three weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analyzed in a cohort of poorly-controlled asthmatics. Results Total airway inflammation following HDM did not differ between DarcΔE2 and WT mice. At 24 hours, DarcΔE2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in DarcΔE2 but persisted in WT mice. In poorly-controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37–7.27), p=0.0062). Conclusions and Clinical Relevance Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.

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Section: Discussioncontrasting

confidence: 99%

Section: Darc Snps Are Associated With Symptoms and Healthcare Utilcontrasting

confidence: 74%

The Duffy antigen receptor for chemokines regulates asthma pathophysiology

Chapman

Mougey

Velden

et al. 2017

Clin Experimental Allergy

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“…Here, neutrophils in NiV-B-infected lung grafts from reconstituted mice were found, in agreement with data from previous studies (2, 10, 18, 50-52), and were detected concomitant with secreted mediators that can recruit them, including G-CSF, GM-CSF, IL-6, IL-8, and IP-10 (53, 54). Interestingly, neutrophils can generate oxidative stress by an oxidative burst that releases ROS and MPO (55,56), the levels of which in the lung have been shown to be positively correlated with the level of MDA, which was increased in our study as well. The conclusive role of neutrophils in oxidative stress induction in NiV-B-infected lung grafts from reconstituted mice will require additional studies.…”

Section: Resultssupporting

confidence: 68%

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

Escaffre

Saito

Juelich

et al. 2017

J Virol

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Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/␥ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune systemreconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh strain induced cytopathic lesions in lung grafts similar to those described in patients irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltration in the small airways and alveolar area, induced oxidative stress, and triggered the production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.

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“…We also found that numbers of neutrophils in BAL were increased at 7 d and 21 d after exposure of mice to WTC dust. These cells are known to contribute to oxidative stress induced by organic dust and other particulate matter, and they may play a similar role in the pulmonary response to WTC dust (Mantecca et al, 2010; McGovern et al, 2015; McGovern et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

Sunil

Vayas

Fang

et al. 2017

Experimental and Molecular Pathology

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Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20 μg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3 days, a response which persisted for at least 21 days. Whereas matrix metalloproteinase was upregulated 7 days post-WTC dust exposure, IL-6RA1 was increased at 21 days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3 days, lysine K27 at 7 days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21 days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3 days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21 days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies.

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Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness

Abstract: Adner M. Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness. Am

Cited by 25 publications

References 47 publications

The Duffy antigen receptor for chemokines regulates asthma pathophysiology

The Duffy antigen receptor for chemokines regulates asthma pathophysiology

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

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