Separation of bronchoconstriction from increased ventilatory drive in a nonhuman primate model of chronic allergic asthma

Abstract

The relationship between allergen-induced ventilatory drive and bronchoconstriction was investigated in dust mite-sensitive cynomolgus macaques periodically exposed to low doses of aerosolized antigen for up to 5.5 yr. Initially, the animals responded to aerosolized dust mite allergen at a concentration of 350 arbitrary units (AU)/ml with simultaneous increases in lung resistance (RL) and respiratory rate (RR). With time, RL and RR became differentially sensitive to allergen provocation. At the end of the study period, aerosolized allergen at a concentration of 15 AU/ml doubled RR without increasing RL. When mechanically ventilated to maintain tidal volume, higher concentrations of allergen could be delivered, and RL increased. Inhaled disodium cromoglycate and intravenous diphenhydramine attenuated the increase in RR, indicating that allergen-induced release of histamine and activation of H(1) receptors mediated the response. Inhaled beta-adrenergic agonists attenuated the RR response to dust mite and to direct histamine provocation. These results demonstrate that chronic periodic allergen challenge increases the allergic sensitivity of histamine-dependent reflexes controlling ventilatory drive. Activation of these reflexes is independent of overt bronchoconstriction, but can be inhibited by beta-adrenergic agonists, indicating that beta-adrenergic agonists exert their effect independent of bronchodilation.

Modelling asthma in macaques: longitudinal changes in cellular and molecular markers

“…Nonhuman primates are more similar to humans in their genetics, anatomy, development and responses to pulmonary allergen challenge than other species. These animals are long-lived and can manifest symptoms of relapsing or remitting allergic asthma for years [2,3,6], thereby providing a penultimate model for assessing safety and …”

“…A small number of primate studies have used clinically meaningful aeroallergens, such as ragweed [11] or house dust mite (HDM) delivered in aerosol form [6,12,13]. PLOPPER and HYDE [3] addressed the validity of these models at the anatomical and cellular levels, and ZOU et al [14] documented changes in gene expression by microarray profiling following acute challenge with allergen.…”

Nocturnal thoracoabdominal asynchrony in house dust mite-sensitive nonhuman primates

“…Over a 10-year period prior to the study, 38 Cynomolgus macaques were obtained from Alpha Genesis, Inc. (Yemassee, SC) and sensitized to HDM as described previously 33,34. Briefly, the animals were sensitized by intra-peritoneal injections of Dermatophagoides pteronyssinus and Dermatophagoides farinae extract adsorbed to Alum (156 units of each allergen [Greer Laboratories, Lenoir, NC]; Imject Alum [Pierce, Rockford, IL]) at 2–4 week intervals for six months.…”

“…The house dust mite (HDM) model of allergic asthma in Cynomolgus macaques reproduces the key features of human asthma, including elevated serum IgE levels, β-agonist reversible bronchoconstriction, and late-phase eosinophilic inflammation 33. In addition, the airways become hyperresponsive to nonspecific bronchoconstrictors including histamine, methacholine, and adenosine 33,34. CD4 + T lymphocytes and natural killer T cells in bronchoalveolar lavage fluid are increased, and Th2 lymphocyte cytokines are upregulated 35.…”

The Immune Basis of Allergic Lung Disease

“…Consequently, at high respiratory rates, alveolar filling is compromised and dynamic compliance is reduced. This effect is particularly evident and easily measured by pressureeflow analyses of spontaneously breathing allergic animals and humans, as well as with forced oscillatory techniques (Minshall et al, 1996;Van Scott et al, 2004;Van Scott et al, 2005;Metzger, 1990;Oppenheimer et al, 2009).…”