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Novel Therapies for Pneumonia-Associated Severe Asthma Phenotypes

2020; Elsevier BV; Volume: 26; Issue: 11 Linguagem: Inglês

10.1016/j.molmed.2020.07.006

1471-499X

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

Pediatric health and respiratory diseases

Streptococcus pneumoniae is a leading global cause of pneumonia. While asthma is now recognised as a heterogeneous disease, people with severe asthma are fourfold more likely to develop pneumonia. Pneumococcal nasopharyngeal carriage and viral infections frequently coexist in asthmatics. Respiratory viruses will cause bacterial dispersion deeper into the lower airways to cause pneumonia. Type-2 inflammation results in the emergence of alternatively activated macrophages in asthma that are defective at phagocytosing bacteria, which can permit the establishment of lower respiratory tract infections. Excessive neutrophilic inflammation is an inflammatory feature of both pneumonia and severe asthma. Novel therapies that target both neutrophils and type-2 inflammation have the potential to improve the pathological features of severe asthma. Distinct asthma phenotypes are emerging from well-defined cohort studies and appear to be associated with a history of pneumonia. Asthmatics are more susceptible to infections caused by Streptococcus pneumoniae; however, the mechanisms that underlie defective immunity to this pathogen are still being elucidated. Here, we discuss how alternatively activated macrophages (AAMs) in asthmatics are defective in bacterial phagocytosis and how respiratory viruses disrupt essential host immunity to cause bacterial dispersion deeper into the lungs. We also describe how respiratory pathogens instigate neutrophilic inflammation and amplify type-2 inflammation in asthmatics. Finally, we propose novel dual-acting strategies including granulocyte-colony-stimulating factor receptor (G-CSFR) antagonism and specialised pro-resolving mediators (SPMs) to suppress type-2 and neutrophilic inflammation without compromising pathogen clearance. Distinct asthma phenotypes are emerging from well-defined cohort studies and appear to be associated with a history of pneumonia. Asthmatics are more susceptible to infections caused by Streptococcus pneumoniae; however, the mechanisms that underlie defective immunity to this pathogen are still being elucidated. Here, we discuss how alternatively activated macrophages (AAMs) in asthmatics are defective in bacterial phagocytosis and how respiratory viruses disrupt essential host immunity to cause bacterial dispersion deeper into the lungs. We also describe how respiratory pathogens instigate neutrophilic inflammation and amplify type-2 inflammation in asthmatics. Finally, we propose novel dual-acting strategies including granulocyte-colony-stimulating factor receptor (G-CSFR) antagonism and specialised pro-resolving mediators (SPMs) to suppress type-2 and neutrophilic inflammation without compromising pathogen clearance. in contrast to classically activated macrophages polarised by interferon-γ, AAMs are induced by Th2-associated cytokines IL-4 and IL-13. While their role in asthma is debated, AAMs release anti-inflammatory cytokines such as IL-10 and upregulate markers such as arginase, chitinase and found in inflammatory zone 1 (FIZZ1). important phagocytic cells that provide the initial defence against pathogens that enter the airspaces. AMs also clear apoptotic cells during the resolution of inflammation, a process known as efferocytosis. an exclusive receptor for granulocyte-colony-stimulating factor (G-CSF) expressed on mature neutrophils. Interactions between G-CSF and G-CSFR promote neutrophil migration and recruitment. biologically active peptide fragments that ascend from degradation of the extracellular matrix. Matrikines regulate a number of different cellular activities in the lungs including wound repair and leukocyte chemotaxis. an important immune process that promotes phagocytosis. During opsonisation, opsonins decorate the surface of pathogens, making them more identifiable by phagocytic cells. a pore-forming toxin and well-known pneumococcal virulence factor. the prompt release of reactive oxygen species by phagocytic cells such as macrophages. It is frequently associated with the elimination of phagocytosed pathogens. a type of asthma that remains uncontrolled despite the suitable use of maximally applied therapy. This definition also encompasses individuals whose symptoms deteriorate following a decrease in high-dose treatment. a large class of anti-inflammatory molecules synthesised from essential fatty acids. SPMs facilitate the resolution of inflammation by counter regulating proinflammatory signalling. process characterised by the release of IL-4, IL-5, and IL-13 by Th2 cells. These cytokines promote B cell isotype switching to IgE, increased mucus production, and the recruitment of eosinophils to the airways, which are classic features of allergy- induced asthma.