Recombinant human deoxyribonuclease therapy improves airway resistance and reduces DNA extracellular traps in a murine acute asthma model

Cunha, Aline Andrea da; Nuñez, Nailê Karine; Souza, Rodrigo Matos de; Vargas, Mauro Henrique Moraes; Silveira, Josiane Silva; Antunes, Géssica Luana; Durante, Laíse da Silva; Porto, Bárbara Nery; Marczak, Elisa Simon; Jones, Marcus Herbert; Pitrez, Paulo Márcio

doi:10.3109/01902148.2016.1143537

Cited by 33 publications

(38 citation statements)

References 25 publications

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“…This treatment reduces the risk of disease exacerbation and improves overall outcome for the patient ( 98 – 100 ). Consistent with those findings, DNase treatment and removal of NETs has also been shown to improve lung function in murine asthma models ( 101 ).…”

Section: Nets and Diseasesupporting

confidence: 64%

NET Confusion

et al. 2016

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Neutrophils are arguably the most important white blood cell for defense against bacterial and fungal infections. These leukocytes are produced in high numbers on a daily basis in humans and are recruited rapidly to injured/infected tissues. Phagocytosis and subsequent intraphagosomal killing and digestion of microbes have historically been the accepted means by which neutrophils carry out their role in innate host defense. Indeed, neutrophils contain and produce numerous cytotoxic molecules, including antimicrobial peptides, proteases, and reactive oxygen species, that are highly effective at killing the vast majority of ingested microbes. On the other hand, it is these characteristics – high numbers and toxicity – that endow neutrophils with the potential to injure and destroy host tissues. This potential is borne out by many inflammatory processes and diseases. Therefore, it is not surprising that host mechanisms exist to control virtually all steps in the neutrophil activation process and to prevent unintended neutrophil activation and/or lysis during the resolution of inflammatory responses or during steady-state turnover. The notion that neutrophil extracellular traps (NETs) form by cytolysis as a standard host defense mechanism seems inconsistent with these aforementioned neutrophil “containment” processes. It is with this caveat in mind that we provide perspective on the role of NETs in human host defense and disease.

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Section: Nets and Diseasesupporting

confidence: 64%

NET Confusion

et al. 2016

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“…A subgroup of patients expressed a high level of neutrophils and NETs, in which the extracellular mtDNA was associated with NE 97 . In an animal model of asthma, the treatment with deoxyribonuclease, which cleaves extracellular DNA, resulted in an improvement of airway resistance and abolished extracellular DNA content in BALF as well as goblet cell hyperplasia 98 . Peripheral blood eosinophils from patients with severe eosinophilic asthma (SEA) may be more activated to produce EETs than those from patients with nonsevere asthma (NSA), which further induces inflammation in asthmatic airways 99 .…”

Section: Eets In Asthma and Rhinosinusitismentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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“…[42] Currently, asthma can be divided into four distinct phenotypes termed eosinophilic, neutrophilic, mixed granulocytic, and pauci-granulocytic phenotypes by investigating granulocyte infiltration in induced sputum. [43] Although the majority of patients with eosinophilic asthma are sensitive to corticosteroids, there is recognition that some asthmatics, particularly those who have severe disease and are resistant to corticosteroids, have elevated neutrophil counts in their airways.…”

Section: Neutrophil Extracellular Traps and Asthmamentioning

confidence: 99%

“…[53] demonstrated that CF patients treated with DNase resulted in an increasing in NE activity and subsequent injury to the lung tissue. In a mouse model of asthma,[42] it was observed that extracellular DNA in mucous was involved in lower airway obstruction in an ovalbumin-induced model of asthma. In particular, lung functionally was improved by means of treatment with an intranasal administration of recombinant human DNase.…”

Section: Neutrophil Extracellular Traps and Asthmamentioning

confidence: 99%

“…In particular, lung functionally was improved by means of treatment with an intranasal administration of recombinant human DNase. [42] This study provides a novel viewpoint that the use of recombinant human DNase is a potential strategy for preventing tissue damage in asthmatics when the NET formation appears to be detrimental.…”

Section: Neutrophil Extracellular Traps and Asthmamentioning

confidence: 99%

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Role of Neutrophil Extracellular Traps in Asthma and Chronic Obstructive Pulmonary Disease

Liu

Wang

et al. 2017

Chinese Medical Journal

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Objective:Asthma and chronic obstructive pulmonary disease (COPD) are representative chronic inflammatory airway diseases responsible for a considerable burden of disease. In this article, we reviewed the relationship between neutrophil extracellular traps (NETs) and chronic inflammatory airway diseases.Data Sources:Articles published up to January 1, 2017, were selected from the PubMed, Ovid Medline, Embase databases, with the keywords of “asthma” or “pulmonary disease, chronic obstructive”, “neutrophils” and “extracellular traps.”Study Selection:Articles were obtained and reviewed to analyze the role of NETs in asthma and COPD.Results:NETs are composed of extracellular DNA, histones, and granular proteins, which are released from activated neutrophils. Multiple studies have indicated that there are a large amount of NETs in the airways of asthmatics and COPD patients. NETs can engulf and kill invading pathogens in the host. However, disordered regulation of NET formation has shown to be involved in the development of asthma and COPD. An overabundance of NETs in the airways or lung tissue could cause varying degrees of damage to lung tissues by inducing the death of human epithelial and endothelial cells, and thus resulting in impairing pulmonary function and accelerating the progress of the disease.Conclusions:Excessive NETs accumulate in the airways of asthmatics and COPD patients. Although NETs play an essential role in the innate immune system against infection, excessive components of NETs can cause lung tissue damage and accelerate disease progression in asthmatics and COPD patients. These findings suggest that administration of NETs could be a novel approach to treat asthma and COPD. Mechanism studies, clinical practice, and strategies to regulate neutrophil activation or directly interrupt NET function in asthmatics and COPD patients are desperately needed.

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Recombinant human deoxyribonuclease therapy improves airway resistance and reduces DNA extracellular traps in a murine acute asthma model

Abstract: Our results suggest that extracellular DNA in mucus play a role in lower airways obstruction in OVA asthma protocol and that the treatment with rhDNase improved lung function and DNA extracellular traps, with no direct cellular anti-inflammatory effects.

Cited by 33 publications

References 25 publications

NET Confusion

NET Confusion

In vivo evidence for extracellular DNA trap formation

Role of Neutrophil Extracellular Traps in Asthma and Chronic Obstructive Pulmonary Disease

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