The non-human primate as a model for studying COPD and asthma
Introduction
The purpose of this review is to assess the utility of non-human primates as models for chronic airways disease in humans. We will address the current status of our understanding of a series of critical issues regarding the utility of this model and its appropriateness for defining mechanisms as they relate to disease processes in human airways. Two diseases we will focus on are asthma and chronic obstructive pulmonary disease. We will address the biology of the airway within the conceptual framework of the epithelial-mesenchymal trophic unit (EMTU). The basis of this concept is that all of the cellular and acellular compartments within the airway wall have a close interaction through a series of extra cellular signaling cascades which establish a dynamic steady state. This steady state responds to injury to one component by changing the signaling patterns and the basic functions of all components. We will evaluate the differences between species in the organization of the airway wall in adults, compare differences in postnatal development of the airways by species, compare airway remodeling associated with asthma and airway-specific responses to inflammatory agents.
Section snippets
The concept of EMTU
The concept of the EMTU was developed as a framework for defining the cellular and metabolic mechanisms regulating the response to injury in a complex biological structure such as the tracheobronchial airway tree [1], [2]. Each segment, or airway generation, within the branching tracheobronchial airway tree is addressed as a unique biological entity whose properties may differ from those of neighboring branches and the intervening branch points. The portions of the airways between branch points
Architecture
As illustrated in Fig. 2, the tracheobronchial conducting airways form a complex series of branching tubes which extend to the gas exchange area. The more proximal of these branches, bronchi, are usually characterized by their histological composition, including the presence of mucus and basal cells in the epithelium, some mucosal glands in the interstitium, and a significant amount of cartilage in the interstitial spaces. More distally, the bronchioles have a thinner wall, the complexity of
Epithelial differentiation
In adult mammals, at least eight cell phenotypes line the tracheobronchial conducting airways, including ciliated cells, basal cells, mucous goblet cells, serous cells, Clara cells, small mucous granule cells, brush cells, neuroendocrine cells, and a number of undifferentiated or partially differentiated phenotypes which have not been well characterized. Humans and other primates share a mixture of cell phenotypes not found in non-primate species [7]. In rhesus monkeys [16], [17] epithelial
Mucociliary epithelium in rhesus monkeys
The tracheobronchial airways of rhesus monkeys have been used extensively to define the biology of mucociliary epithelium. The capability of the airways to metabolically activate xenobiotics has been evaluated for both the cytochrome P-450 monooxygenases [29], [30] and flavin-containing monooxygenases [31], [32]. The composition of secretory products has been defined for complex carbohydrates in surface epithelium and glands throughout the airway tree in adults [for] (complex carbohydrates) [33]
Airway-specific responses to inflammatory agents
A model of experimental allergic asthma, using a known human allergen, house dust mite, has been validated for rhesus monkeys [54], [55]. Ozone exposure exacerbates the impact of allergen exposure on this model when applied to infant monkeys [56]. This includes modulating hypercontractility of airway smooth muscle tested in vitro[57] and modulated by 5-lipoxygenase [58] and a variety of other mediators [59], [60]. This exposure disrupts airway growth [61] and the development and function of a
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