Novel Therapies for Pneumonia-Associated Severe Asthma Phenotypes

Papanicolaou, Angelica; Wang, Hao; Satzke, Catherine; Vlahos, Ross; Wilson, Nick; Bozinovski, Steven

doi:10.1016/j.molmed.2020.07.006

Cited by 6 publications

(4 citation statements)

References 95 publications

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“…Based on these findings, we then evaluated P140 activity using the HDM-induced allergic airway inflammation model. Evaluating experimental therapeutics using this model was pivotal in our study, as it could lead to new options for asthma patients whose symptoms are not well managed with current treatment options [ 49 ]. HDM is an immunologically complex allergen, which can stimulate both the innate and adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

Daubeuf

Schall

Petit-Demoulière

et al. 2021

Cells

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The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.

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Section: Discussionmentioning

confidence: 99%

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

Daubeuf

Schall

Petit-Demoulière

et al. 2021

Cells

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“…Also, the neutralization of the G-CSF receptor (G-CSFR) attenuated neutrophilic asthma and mucus secretion in a murine model [ 11 ]. Together, these results suggest the role of G-CSF as a critical player in neutrophilic asthma development and exacerbation [ 12 ]. Despite the suggested critical roles of G-CSF in neutrophilic asthmatic pathogenesis, little is known about the regulators of the production of G-CSF in severe neutrophilic asthma.…”

Section: Introductionmentioning

confidence: 99%

Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation

2022

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Granulocyte colony-stimulating factor (G-CSF) has been suggested to be closely associated with neutrophilic asthma pathogenesis. However, little is known about the factors regulating the production of G-CSF in neutrophilic asthma. We previously reported that a leukotriene B4 receptor 2, BLT2, played an important role in neutrophilic airway inflammation. Therefore, in the current study, we investigated whether BLT2 plays a role in the production of G-CSF in lipopolysaccharide/ovalbumin (LPS/OVA)-induced steroid-resistant neutrophilic asthma. The data showed that BLT2 critically mediated G-CSF production, contributing to the progression of neutrophilic airway inflammation. We also observed that 12-lipoxygenase (12-LO), which catalyzes the synthesis of the BLT2 ligand 12(S)-HETE, was also necessary for G-CSF production. Together, these results suggest that the 12-LO-BLT2-linked signaling network is critical for the production of G-CSF, contributing to the development of neutrophilic airway inflammation. Our findings can provide a potential new target for the therapy of severe neutrophilic asthma.

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“…In contrast, HDM-induced allergic mice are unable to mount an effective antibacterial response, as allergy impairs neutrophil recruitment resulting in bacterial invasion and dissemination ( 115 ). These differences in antibacterial immunity may be due to methodological variations such as the use of different allergen models, different Spn serotypes, and infectious doses and regimens used ( 116 ).…”

Section: Impact Of Bacterial Infections In Asthma Pathogenesismentioning

confidence: 99%

Impact of Therapeutics on Unified Immunity During Allergic Asthma and Respiratory Infections

Flores-Torres

Samarasinghe

2022

Front. Allergy

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Graphical AbstractInterplay between infectious agents and allergic milieu. Respiratory infections caused by viruses, bacteria and fungi play an important role in asthma pathogenesis. The immune milieu in allergic asthma may be both defective and protective during respiratory infections. Some bacteria are linked to steroid-resistant neutrophilic asthma and an aberrant immune response. Thermotolerant fungi generally induces a T2 immune response in asthma and are linked to asthma severity and higher corticosteroid requirement. Steroid-resistant neutrophilic asthma is associated with increased airway bacterial burden and reduced bacterial diversity. Corticosteroids and antibiotics induce dysbiosis in asthmatics, which may cause immune system alterations. Biologics and antivirals may be beneficial in some patients. However, the effect of eosinophil depletion on antiviral immunity in asthmatics remains unknown. Influenza and COVID-19 vaccination are recommended in asthmatics, but pneumococcal vaccine benefits are still under debate.

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Novel Therapies for Pneumonia-Associated Severe Asthma Phenotypes

Cited by 6 publications

References 95 publications

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation

Impact of Therapeutics on Unified Immunity During Allergic Asthma and Respiratory Infections

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