The Role of Toll-like Receptors in Age-Associated Lung Diseases

Volkova, Maria; Zhang, Yitao; Shaw, Albert C.; Lee, Patricia

doi:10.1093/gerona/glr226

Cited by 18 publications

(11 citation statements)

References 76 publications

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“…Telomere dysfunction and senescence associated pathways have been described in explants studied from patients with bronchiectasis [18]. As such, this represents an important area of future interest and research [19][20][21].…”

Section: Ageing and Its Impact On Bronchiectasismentioning

confidence: 93%

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

et al. 2018

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Bronchiectasis is a disease associated with chronic progressive and irreversible dilatation of the bronchi and is characterised by chronic infection and associated inflammation. The prevalence of bronchiectasis is age-related and there is some geographical variation in incidence, prevalence and clinical features. Most bronchiectasis is reported to be idiopathic however post-infectious aetiologies dominate across Asia especially secondary to tuberculosis. Most focus to date has been on the study of airway bacteria, both as colonisers and causes of exacerbations. Modern molecular technologies including next generation sequencing (NGS) have become invaluable tools to identify microorganisms directly from sputum and which are difficult to culture using traditional agar based methods. These have provided important insight into our understanding of emerging pathogens in the airways of people with bronchiectasis and the geographical differences that occur. The contribution of the lung microbiome, its ethnic variation, and subsequent roles in disease progression and response to therapy across geographic regions warrant further investigation. This review summarises the known geographical differences in the aetiology, epidemiology and microbiology of bronchiectasis. Further, we highlight the opportunities offered by emerging molecular technologies such as -omics to further dissect out important ethnic differences in the prognosis and management of bronchiectasis.

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Section: Ageing and Its Impact On Bronchiectasismentioning

confidence: 93%

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

et al. 2018

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“…During severe infections in older adults and aged mice, profound neutrophil dysfunction has been described across all effector functions. Toll-like receptor signalling (implicated in neutrophil ROS generation, cytokine production and increased survival) is decreased in older age 41. The accuracy of neutrophil migration is impaired in older adults with CAP, and this remains diminished for at least 6 weeks following the episode of CAP,33 a pattern not seen in neutrophils isolated from young adults with CAP.…”

Section: Host Immune System At the Extremes Of Agementioning

confidence: 99%

Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age

Grudzinska

Brodlie

Scholefield

et al. 2019

Thorax

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"Science means constantly walking a tight rope" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.

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“…Triggering of these receptors leads to the induction of cytokine and chemokine production and maturation of some cell types, such as dendritic cells (DCs) . Several studies have shown that ageing leads to reductions in TLR expression (both mRNA and protein), signalling and downstream cytokine production in some cell types and models . Unfortunately, there is a paucity of information regarding changes due to advanced age in PRR‐mediated signalling after influenza virus infection.…”

Section: Age‐related Defects In Innate Immune Receptorsmentioning

confidence: 99%

Innate immune responses in the ageing lung

Boe

Boule

Kovacs

2016

Clinical and Experimental Immunology

103

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SummaryThe world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age-related dysfunction of the immune system resulting from low-grade chronic inflammation known as 'inflamm-ageing'. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life-threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age-related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age-specific therapies to address lung infections in such a vulnerable population.

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The Role of Toll-like Receptors in Age-Associated Lung Diseases

Cited by 18 publications

References 76 publications

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age

Innate immune responses in the ageing lung

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