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A significant proportion of chronic obstructive pulmonary disease exacerbations are strongly associated with rhinovirus infection (HRV). In this study, we combined long-term cigarette smoke exposure with HRV infection in a mouse model. Our aim was to better understand the effects of HRV infection on such exacerbations, using a realistic method for generating a COPD-like phenotype. After 12-weeks of cigarette smoke exposure, adult female BALB/c mice were infected with HRV-1A and three days later we assessed a range of outcomes including lung volume and function, collected lung tissue for measurement of viral titre, bronchoalveolar lavage for assessment of pulmonary inflammation and levels of key mediators, and fixed lungs for stereological structural analyses. Cigarette smoke exposure alone significantly increased total cells and macrophages, and reduced MIP-2 in bronchoalveolar lavage. HRV-1A infection alone increased neutrophilic inflammation, IP-10 and total protein in lavage and also increased specific airway resistance measured at functional residual capacity. Cigarette smoke and HRV-1A together impacted various lung structural parameters including increasing stereological lung volume. Our results show that long-term cigarette smoke exposure and HRV-1A infection both individually impact respiratory outcomes and combine to alter aspects of lung structure in a mouse model, thus providing insight into the development of future mechanistic studies and appropriate interventions in human disease.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.Copyright © 2020 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.

Chronic allergic inflammatory diseases are a major cause of morbidity, with allergic asthma alone affecting over 300 million people worldwide. Epidemiological studies demonstrate that environmental stimuli are associated with either the promotion or prevention of disease. Major reductions in asthma prevalence are documented in European and US farming communities. Protection is associated with exposure of mothers during pregnancy to microbial breakdown products present in farm dusts and unprocessed foods and enhancement of innate immune competence in the children. We sought to develop a scientific rationale for progressing these findings toward clinical application for primary disease prevention. Treatment of pregnant mice with a defined, clinically approved immune modulator was shown to markedly reduce susceptibility of their offspring to development of the hallmark clinical features of allergic airway inflammatory disease. Mechanistically, offspring displayed enhanced dendritic cell–dependent airway mucosal immune surveillance function, which resulted in more efficient generation of mucosal-homing regulatory T cells in response to local inflammatory challenge. We provide evidence that the principal target for maternal treatment effects was the fetal dendritic cell progenitor compartment, equipping the offspring for accelerated functional maturation of the airway mucosal dendritic cell network following birth. These data provide proof of concept supporting the rationale for developing transplacental immune reprogramming approaches for primary disease prevention.

Studies of traditional European and US farming populations have documented major reductions in asthma prevalence in children of mothers exposed during pregnancy to microbial breakdown products present in farm dust and unprocessed foods. The mechanisms driving protection appear associated with enhancement of innate immune competence in the offspring leading to optimisation of immunoregulatory and effector cell function. The potential to therapeutically harness this environmental phenomenon represents a plausible strategy in the primary prevention of asthma. Using preclinical mouse models, we sought to identify if a safe ǀ microbial-derived immunomodulatory therapeutic could recapitulate the "farm effect" phenomenon. We demonstrate that maternal oral treatment during pregnancy with the clinically-approved bacterial-derived immunomodulator OM-85, markedly reduces the susceptibility of offspring to development of allergic airways inflammation initiated at weaning. This was exemplified by attenuation of granulocytic infiltration and airways hyperresponsiveness following airways challenge. Protection was linked to the recruitment of T-regulatory cells to airways mucosa exhibiting enhanced CTLA-4 and Foxp3 expression, with parallel attenuation of local cDC trafficking to airway draining lymph nodes and inflammation associated recruitment and activation. Moreover, these offspring display a striking attenuation of the inflammatory response in the bone marrow myeloid precursor compartments, consistent with the reduced mobilisation of cDC bone marrow reserves and granulocytic accumulation within the airways. The mechanistic actions of OM-85 on bone marrow precursors could be traced back to in utero development, whereby maternal OM-85 treatment boosts myeloid progenitor cells within fetal bone marrow whilst simultaneously accelerating DC functional immune competence as evident by upregulated IA/IE expression. In vitro validation of OM-85-induced immunomodulatory effects on bone

Immunological homeostasis in the respiratory tract is thought to require balanced interactions between networks of dendritic cell (DC) subsets in lung microenvironments in order to regulate tolerance or immunity to inhaled antigens and pathogens. Influenza A virus (IAV) poses a serious threat of long-term disruption to this balance through its potent pro-inflammatory activities. In this study, we have used a BALB/c mouse model of A/PR8/34 H1N1 Influenza Type A Virus infection to examine the effects of IAV on respiratory tissue DC subsets during the recovery phase following clearance of the virus. In adult mice, we found differences in the kinetics and activation states of DC residing in the airway mucosa (AMDC) compared to those in the parenchymal lung (PLDC) compartments. A significant depletion in the percentage of AMDC was observed at day 4 post-infection that was associated with a change in steady-state CD11b+ and CD11b− AMDC subset frequencies and significantly elevated CD40 and CD80 expression and that returned to baseline by day 14 post-infection. In contrast, percentages and total numbers of PLDC were significantly elevated at day 14 and remained so until day 21 post-infection. Accompanying this was a change in CD11b+and CD11b− PLDC subset frequencies and significant increase in CD40 and CD80 expression at these time points. Furthermore, mice infected with IAV at 4 weeks of age showed a significant increase in total numbers of PLDC, and increased CD40 expression on both AMDC and PLDC, when analysed as adults 35 days later. These data suggest that the rate of recovery of DC populations following IAV infection differs in the mucosal and parenchymal compartments of the lung and that DC populations can remain disrupted and activated for a prolonged period following viral clearance, into adulthood if infection occurred early in life.

It is widely accepted that atopic asthma depends on an allergic response in the airway, yet the immune mechanisms that underlie the development of airway hyperresponsiveness (AHR) are poorly understood. Mouse models of asthma have been developed to study the pathobiology of this disease, but there is considerable strain variation in the induction of allergic disease and AHR. The aim of this study was to compare the development of AHR in BALB/c, 129/Sv, and C57BL/6 mice after sensitization and challenge with ovalbumin (OVA). AHR to methacholine was measured using a modification of the forced oscillation technique in anesthetized, tracheostomized mice to distinguish between airway and parenchymal responses. Whereas all strains showed signs of allergic sensitization, BALB/c was the only strain to develop AHR, which was associated with the highest number of activated (CD69+) CD4+ T cells in the airway wall and the highest levels of circulating OVA-specific IgG1. AHR did not correlate with total or antigen-specific IgE. We assessed the relative contribution of CD4+ T cells and specific IgG1 to the development of AHR in BALB/c mice using adoptive transfer of OVA-specific CD4+ T cells from DO11.10 mice. AHR developed in these mice in a progressive fashion following multiple OVA challenges. There was no evidence that antigen-specific antibody had a synergistic effect in this model, and we concluded that the number of antigen-specific T cells activated and recruited to the airway wall was crucial for development of AHR.

Adoptive transfer of activated T cells has been shown to induce allergic responses in the lung, however, direct physiological evidence of whether these T cells home to the airways is lacking. This study aimed to determine the role of CD4+ T cells in the generation of airway hyperresponsiveness (AHR) in mouse models of asthma. Methods: (1) 129/Sv, C57BL/6 and BALB/c mice were sensitized and challenged with ovalbumin (OVA). AHR, inflammatory cells, serum IgE and IgG1 and the number of CD4+ CD69+ T cells in the trachea and peripheral lung were measured. (2) DO11.10 transgenic T cells that recognize OVAwere transferred to naïve BALB/c recipients. Recipient mice were primed and challenged with OVAand assessed forAHR and serum antibodies. (3) Naïve BALB/c mice were passively sensitized with high titre IgE/IgG1 titre serum, challenged with OVA and assessed for AHR. Results: (1) AHR to inhaled methacholine (MCh) was induced by OVA in BALB/c mice only. This correlated with the presence of CD4+ CD69+ T cells and IgG1 . (2) After 5 OVA challenges naïve BALB/c mice primed with DO11.10 T cells demonstrated AHR (p=0.049) to MCh. (3) Passive transfer of high titre IgE/IgG1 serum did not result in AHR. Conclusions: The presence of AHR in BALB/c mice was linked to the numbers of CD4+ CD69+ T cells and IgG1. Adoptive transfer of T cells that recognize OVA resulted in AHR following challenge suggesting that these T cells traffic to the airway after challenge. This could not be replicated by passively sensitizing mice with high IgE/IgG1 titre serum alone. This study highlighted the potential role of CD4+ T cells in the development of AHR and further studies using this system may be able to dissect the mechanism by which this occurs.