Alexander N. Larcombe

Environmental Correlates of Physiological Variables in Marsupials

We analyzed body temperature (Tb), basal metabolic rate (BMR), wet thermal conductance (Cwet), and evaporative water loss (EWL) of marsupials by conventional and phylogenetically corrected regression. Allometric effects were substantial for BMR, Cwet, and EWL but not Tb. There was a strong phylogenetic signal for mass and all physiological traits. A significant phylogenetic signal remained for BMR, Cwet, and EWL even after accounting for the highly significant phylogenetic signal of mass. Tb, BMR, Cwet, and EWL allometric residuals were correlated with some diet, distribution, and climatic variables before and after correction for phylogeny. Tb residuals were higher for marsupials from arid environments (high Ta and more variable rainfall). The fossorial marsupial mole had a lower‐than‐expected Tb residual. The allometric slope for BMR was 0.72–0.75. Residuals were consistently related to distribution aridity and rainfall variability, with species from arid and variable rainfall habitats having a low BMR, presumably to conserve energy in a low‐productivity environment. The nectarivorous honey possum had a higher‐than‐expected BMR. For Cwet, the allometric slope was 0.55–0.62; residuals were related to diet, with folivores having low and insectivores high Cwet residuals. The allometric slope for EWL was 0.68–0.73. EWL residuals were consistently correlated with rainfall variability, presumably facilitating maintenance of water balance during dry periods.

Ovalbumin-sensitized mice are good models for airway hyperresponsiveness but not acute physiological responses to allergen inhalation

Background Asthma is a chronic inflammatory disease that is characterized clinically by airway hyperresponsiveness (AHR) to bronchoconstricting agents. The physiological response of the asthmatic lung to inhaled allergen is often characterized by two distinct phases: an early‐phase response (EPR) within the first hour following exposure that subsides and a late‐phase response (LPR) that is more prolonged and may occur several hours later. Mouse models of asthma have become increasingly popular and should be designed to exhibit an EPR, LPR and AHR.

Suppression of the asthmatic phenotype by ultraviolet B-induced, antigen-specific regulatory cells

Background Over recent decades, there has been a significant global increase in the prevalence of asthma, an inflammatory disease of the respiratory system. While ultraviolet radiation (UV) has been used successfully in the treatment of inflammatory conditions such as psoriasis, studies of UV‐induced regulation of allergic respiratory responses have been rare, and have not analysed in vivo measurements of airway hyperresponsiveness (AHR) or the antigen specificity of the UV‐induced effects.

Boosting airway T-regulatory cells by gastrointestinal stimulation as a strategy for asthma control

The hallmark of atopic asthma is transient airways hyperresponsiveness (AHR) preceded by aeroallergen-induced Th-cell activation. This is preceded by upregulation of CD86 on resident airway dendritic cells (DCs) that normally lack competence in T-cell triggering. Moreover, AHR duration is controlled via T-regulatory (Treg) cells, which can attenuate CD86 upregulation on DC. We show that airway mucosal Treg/DC interaction represents an accessible therapeutic target for asthma control. Notably, baseline airway Treg activity in sensitized rats can be boosted by microbe-derived stimulation of the gut, resulting in enhanced capacity to control CD86 expression on airway DC triggered by aeroallergen and accelerated resolution of AHR.

Sexual dimorphism in lung function responses to acute influenza A infection

Please cite this paper as: Larcombe et al. (2011) Sexual dimorphism in lung function responses to acute influenza A infection. Influenza and Other Respiratory Viruses 5(5), 334–342.

Effects of Temperature on Metabolism, Ventilation, and Oxygen Extraction in the Southern Brown Bandicoot Isoodon obesulus (Marsupialia: Peramelidae)

The effects of ambient temperatures (Ta) from 10° to 35°C on metabolism, ventilation, and oxygen extraction were examined for the southern brown bandicoot (Isoodon obesulus). Oxygen consumption (V̇o2) followed the pattern typical for endotherms, decreasing with increasing Ta from 10° to 25°C. It did not significantly change between Ta = 25° and 35°C (the thermoneutral zone). V̇o2 was approximately 2.4 times higher at Ta = 10°C (0.967 mL O2 g−1 h−1) compared with basal (0.410 mL O2 g−1 h−1) at Ta = °C. While the metabolic rates of the bandicoots were basal at Ta = 30°C, respiratory frequency (fR) was 24.6 breaths min−1, tidal volume (VT) was 7.79 mL, minute volume (V̇i) was 191.3 mL min−1, and oxygen extraction efficiency (Eo2) was 26.8%. Increased V̇o2 at Ta ≤ 25°C was associated with a large increase in V̇i due to increases in VT and fR. A greater proportion of the change was due to the increase in tidal volume. Eo2 was constant at ∼26% for all Ta up to and including 30°C. At Ta = 35°C, Eo2 decreased to 17.7%, fR increased to 35.6 breaths min−1, and VT decreased to 7.22 mL. The metabolic and ventilatory physiology of the southern brown bandicoot are typical of an unspecialised medium‐sized marsupial.

Early Life Arsenic Exposure and Acute and Long-term Responses to Influenza A Infection in Mice

Background: Arsenic is a significant global environmental health problem. Exposure to arsenic in early life has been shown to increase the rate of respiratory infections during infancy, reduce childhood lung function, and increase the rates of bronchiectasis in early adulthood. Objective: We aimed to determine if early life exposure to arsenic exacerbates the response to early life influenza infection in mice. Methods: C57BL/6 mice were exposed to arsenic in utero and throughout postnatal life. At 1 week of age, a subgroup of mice were infected with influenza A. We then assessed the acute and long-term effects of arsenic exposure on viral clearance, inflammation, lung structure, and lung function. Results: Early life arsenic exposure reduced the clearance of and exacerbated the inflammatory response to influenza A, and resulted in acute and long-term changes in lung mechanics and airway structure. Conclusions: Increased susceptibility to respiratory infections combined with exaggerated inflammatory responses throughout early life may contribute to the development of bronchiectasis in arsenic-exposed populations. Citation: Ramsey KA, Foong RE, Sly PD, Larcombe AN, Zosky GR. 2013. Early life arsenic exposure and acute and long-term responses to influenza A infection in mice. Environ Health Perspect 121:1187–1193; http://dx.doi.org/10.1289/ehp.1306748

Sensitizing and Th2 Adjuvant Activity of Cysteine Protease Allergens

Background: Innate properties that enhance immune responses might increase the propensity of certain allergens to induce allergic sensitization. Either a direct adjuvant effect or the increased immune response to the allergen could then increase allergic responses to bystander antigens. Here, we report on a model that does not use Th2-skewing adjuvants and yet achieves sensitization solely via the nasal mucosa. Methods: Animals were sensitized with either enzymatically active, inactive or non-activated cysteine proteases via the nasal mucosa. Following two sensitization phases, mice were challenged with a higher dose of allergen. For bystander sensitization, mice received recombinant Der p 2 at sensitization in conjunction with the cysteine protease and were challenged with rDer p 2 alone. Sensitization was determined by measuring allergen-specific antibody responses and cytokine and cellular infiltrates into the lungs following challenge. Results: Sensitization for Th2-type lung hypersensitivity for both the cysteine protease and bystander antigens was readily achieved and both were dependent on the proteolytic activity of the allergen. Bystander adjuvant activity was demonstrated for mice that were low IgE responders to the cysteine protease, showing a response independent from the immune response to the enhancing cysteine protease. Airway hyperreactivity was induced in the susceptible NOD strain of mouse, and mice subjected to prolonged administration of papain maintained the ability to produce lung hypersensitivity and Th2-type responses. Conclusions: These experiments demonstrate that cysteine protease activity at low doses can be an adjuvant for respiratory Th2 responses for themselves and bystander antigens in the absence of another adjuvant.

Airway hyperresponsiveness is associated with activated CD4+ T cells in the airways

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 IgG(1). AHR did not correlate with total or antigen-specific IgE. We assessed the relative contribution of CD4(+) T cells and specific IgG(1) 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.

Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice.

Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.