C. G. Plopper

The non-human primate as a model for studying COPD and asthma.

This review evaluates the current status of information regarding the nonhuman primate as an experimental model for defining mechanisms of chronic airways disease in humans, using the concept of the epithelial-mesenchymal trophic unit (EMTU) as a basis for comparison with other laboratory species. All of the cellular and acellular compartments within the walls of tracheobronchial airways which interact as the EMTU are present throughout the airway tree in human and nonhuman primates. The epithelial compartment contains mucous goblet and basal cells in the surface epithelium and submucosal glands within the wall. The interstitial compartment of primates has a prominent subepithelial basement membrane zone (BMZ) with an attenuated fibroblast sheath and cartilage throughout the tree. In primates, there is an extensive transition zone between distal conducting airways and lung parenchyma composed of numerous generations of respiratory bronchioles. None of these features are characteristic of intrapulmonary airways in rodents, whose airways do share ciliated cells, smooth muscle cells, nerve networks, vasculature and inflammatory cell populations with primates. While the numbers of intrapulmonary airway branches are similar for most mammals, branching patterns, which dictate distribution of inhaled materials, are more uniform (dichotomous) in primates and less so (monopodial) in rodents. Development of tracheobronchial airways (both differentiation of the EMTU and overall growth) occurs over an extensive postnatal period (months to years) in primates and a comparably shorter time period (2-3 weeks) in rodents. As with allergic airways disease in humans, experimental exposure of nonhuman primates to a known human allergen, house dust mite, produces extensive remodeling of all compartments of the EMTU: mucous goblet cell hyperplasia, epithelial sloughing, basement membrane zone (BMZ) thickening and reorganization, altered attenuated fibroblast function, subepithelial fibrosis and smooth muscle thickening. Experimental allergic airways disease in nonhuman primates also shares other features with asthmatic humans: positive skin test to allergen; allergen-specific circulating IgE; airway hyper responsiveness to allergen, histamine and methacholine; increased eosinophils, IGE positive cells and mucins in airway exudate; and migratory leukocyte accumulations in the airway wall and lumen. Experimental exposure of nonhuman primates to reactive gases, such as ozone, produces the chronic respiratory bronchiolitis and other airway alterations associated with restricted airflow and chronic respiratory bronchiolitis characteristic of COPD in young smokers. We conclude that nonhuman primate models are appropriate for defining mechanisms as they relate to allergic airways disease and COPD in humans.

Asthma: a comparison of animal models using stereological methods

Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: “what is the most appropriate laboratory animal model for human asthma?” The present authors used stereological methods to assess airways in adults and during post-natal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans. An epithelial–mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments (e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a T-helper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine. In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.