R.Y. Kim

Constitutive production of IL-13 promotes early-life Chlamydia respiratory infection and allergic airway disease.

Deleterious responses to pathogens during infancy may contribute to infection and associated asthma. Chlamydia respiratory infections in early life are common causes of pneumonia and lead to reduced lung function and asthma. We investigated the role of interleukin-13 (IL-13) in promoting early-life Chlamydia respiratory infection, infection-induced airway hyperresponsiveness (AHR), and severe allergic airway disease (AAD). Infected infant Il13−/− mice had reduced infection, inflammation, and mucus-secreting cell hyperplasia. Surprisingly, infection of wild-type (WT) mice did not increase IL-13 production but reduced IL-13Rα2 decoy receptor levels compared with sham-inoculated controls. Infection of WT but not Il13−/− mice induced persistent AHR. Infection and associated pathology were restored in infected Il13−/− mice by reconstitution with IL-13. Stat6−/− mice were also largely protected. Neutralization of IL-13 during infection prevented subsequent infection-induced severe AAD. Thus, early-life Chlamydia respiratory infection reduces IL-13Rα2 production, which may enhance the effects of constitutive IL-13 and promote more severe infection, persistent AHR, and AAD.

Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease.

Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease.

MicroRNA Profiling Reveals a Role for MicroRNA-218-5p in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Methods: We performed miRNA and mRNA profiling using high throughput stem‐loop reverse‐transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never‐smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA‐218‐5p (miR‐218‐5p) was validated by reverse‐transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR‐218‐5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR‐218‐5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis. Measurements and Main Results: Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR‐218‐5p was significantly down‐regulated in smokers without airflow limitation and in patients with COPD compared with never‐smokers. Decreased pulmonary expression of miR‐218‐5p was validated in an independent validation cohort, in cigarette smoke‐exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR‐218‐5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR‐218‐5p in human and murine lung revealed highest expression of miR‐218‐5p in the bronchial airway epithelium. Perturbation experiments with a miR‐218‐5p mimic or inhibitor demonstrated a protective role of miR‐218‐5p in cigarette smoke‐induced inflammation and COPD. Conclusions: We highlight a role for miR‐218‐5p in the pathogenesis of COPD.

A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL+CD11b+ monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

Programming of the lung by early-life infection

Many important human diseases, such as asthma, have their developmental origins in early life. Respiratory infections in particular may alter the course of asthma and may either protect against or promote the development of this disease. It is likely that the nature of the effects depends on the type and age of infection and is determined by the impact of infection on the immune and respiratory systems. Immunity in early life is plastic and can be moulded by antigen encounter, which may enhance or reinforce the asthmatic phenotype of early life, or induce protective responses. Chlamydial respiratory infections have specific effects and may increase asthma severity in early life by promoting systemic interleukin 13 responses and causing permanent changes in lung structure. Respiratory viral infections, such as those of respiratory syncytial virus and rhinovirus, promote pro-asthmatic responses in early life that contribute to the induction of asthma. By contrast, probiotics or infection or exposure to certain bacteria, such as Streptococcus pneumoniae, may have protective effects in asthma by increasing the numbers and activity of regulatory T cells. Here, we review the impact of infections on the developmental origins of asthma. Understanding these effects may lead to new therapeutic approaches for asthma that either target deleterious infections or utilize beneficial ones.

Neonatal respiratory infection and adult re-infection: effect on glucocorticoid and mineralocorticoid receptors in the hippocampus in BALB/c mice

Stressful events during the perinatal period in both humans and animals have long-term consequences for the development and function of physiological systems and susceptibility to disease in adulthood. One form of stress commonly experienced in the neonatal period is exposure to bacterial and viral infections. The current study investigated the effects of live Chlamydia muridarum bacterial infection at birth followed by re-infection in adulthood on hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) and stress response outcomes. Within 24 h of birth, neonatal mice were infected intranasally with C. muridarum (400 inclusion-forming units [ifu]) or vehicle. At 42 days, mice were re-infected (100 ifu) and euthanized 10 days later. In males, infection in adulthood alone had the most impact on the parameters measured with significant increases in GR protein compared to adult infection alone; and significant increases MR protein and circulating corticosterone compared to other treatment groups. Neonatal infection alone induced the largest alterations in the females with results showing reciprocal patterns for GR protein and TH protein. Perinatal infection resulted in a blunted response following adult infection for both males and females across all parameters. The present study demonstrates for the first time that males and females respond differently to infection based on the timing of the initial insult and that there is considerable sex differences in the hippocampal phenotypes that emerge in adulthood after neonatal infection.

NLRP3 inflammasome-mediated, IL-1 beta-dependent inflammatory responses drive severe, steroid-insensitive asthma

Introduction: Studies suggest that 10% of children with an ARI have persistent cough at day 21. There are no studies in Indigenous children who have a high risk of chronic lung disease. We aimed to identify the incidence and outcomes of ARI with cough as a symptom in urban Indigenous children. Methods:This is a prospective study of Indigenous children aged<5 years registered with a primary health service. Children are followed for a period of 12 months via monthly contacts. Children who develop cough as a symptom at any time are followed weekly for 4 weeks to ascertain cough outcomes. Results: To date, 162 children are enrolled, totalling 1065 child-months of observation. Two-hundred ARI episodes with cough have been reported (29.6 episodes/100 child-months at risk). Thirty-four ARIs (17%) have progressed to persistent cough at day 28 in 24 children. Of these, 15 children had 1 episode, 5 had 2, 4 had 3 and 1 had 4 during the follow-up period. The majority of children with persistent cough were diagnosed (by a respiratory physician) with protracted bacterial bronchitis and/or bronchiectasis. Conclusions:The proportion of children developing persistent cough postARI is higher than that currently reported (10%) with the majority suggesting protracted bacterial infection. GrantSupport:AQUTAPAaward, aQCMRIProgramGrant, UQFoundation Research Excellence Award, a QUT Indigenous Health Research StartUpGrant and the NHMRCCRE for LungHealth in Aboriginal and TorresStrait Islander Children. Declaration of Interest: None to Declare