Trends in Molecular Medicine
ReviewNovel Therapies for Pneumonia-Associated Severe Asthma Phenotypes
Section snippets
The Link between Pneumococcal Pneumonia and Asthma
Asthma is a chronic airway inflammatory disease that affects over 300 million people worldwide [1]. Typically, the airways in asthmatic patients have pathological levels of airway remodelling that leads to variable and reversible airflow obstruction manifesting as bronchial hyperresponsiveness [2]. These pathologies are classically driven by a dominant CD4+ T-helper type-2 (Th2) inflammatory response commonly caused by exposures to aeroallergens such as house dust mites (HDMs) [3]. The release
Increased Pneumonia Risk in Distinct Severe Asthma Phenotypes
Asthma is now recognised as a heterogenous disease (Box 1) which can vary in both phenotype and severity. Of the total asthmatic population, it is estimated around 3%–10% suffer from severe asthma [15,16] which can account for up to 60% of asthma-associated healthcare costs [17]. Severe asthmatics are those that require maximal inhaler therapy, namely, the use of high-dose inhaled corticosteroids with or without a systemic corticosteroid [16]. Despite proper inhaler use, an estimated 3.6% of
Immune Response to Combat Streptococcus pneumoniae
Once colonisation of the nasopharynx has been established, varying circumstances afford Spn access to tissues beyond the nasal epithelium. The development of pneumonia is reliant on Spn accessing the lower airways where a bombardment of innate immune responses perpetuates lung injury. During the initial stages of infection, pneumococci encounter the respiratory epithelium which serves as a physical barrier against infection while also promoting leukocyte trafficking and secretion of
Mechanisms Involved in Reduced Bacterial Control in Asthmatics
The relationship between bacteria and asthma is complex and interrelated. For example, the ‘hygiene hypothesis’ is supported by epidemiological studies showing that asthma rates are lower in environments where early life endotoxin levels are elevated, as bacterial molecules can educate the immune system to mount an appropriate and proportionate response to airborne allergens. Consistent with the hygiene hypothesis, Spn antigens attenuate type-2 inflammation in allergic airways disease models.
Exuberant Immune Response to Respiratory Pathogens in Asthmatics
The consequence of repeated aeroallergen sensitisation and increased susceptibility to respiratory pathogens is the persistent recruitment and activation of neutrophils in the background of type-2 allergic inflammation (Figure 1). Neutrophils isolated from individuals with poorly controlled asthma also appear functionally altered compared with well-controlled asthmatics and healthy individuals. For instance, CXCL8 and neutrophil elastase release following fMLF
Novel Approaches in Targeting Neutrophils in Infection-Dependent Severe Asthma
Dual therapy strategies that block type-2 and neutrophilic inflammation without compromising bacterial or viral clearance mechanisms are needed to reduce the burden of severe asthma (Figure 2 and Clinician’s Corner). Currently available anti-inflammatory therapies, such as corticosteroids, treat type-2 inflammation, but they do not specifically target neutrophilic inflammation in asthmatics. The use of corticosteroids has also been shown to increase lung neutrophil survival [78] and is
Concluding Remarks
Independently, asthma and pneumonia constitute a significant global health problem. While there is a complex interplay between the two, it has become increasingly clear that asthmatics are more susceptible to developing pneumonia associated with increased viral–bacterial co-infections and the polarisation towards AAMs (see Outstanding Questions). It is conceivable that repeated incidents of lower respiratory tract infections could mediate the transition to severe asthma. Currently, severe
Acknowledgements
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Disclaimer Statement
S.B. and N.W. have a patent that is relevant to this review.
Glossary
- Alternatively activated macrophages (AAMs)
- 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).
- Alveolar macrophages (AMs)
- important phagocytic cells that provide the initial defence against pathogens that enter the airspaces. AMs
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