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

https://doi.org/10.1016/j.pupt.2008.01.008Get rights and content

Abstract

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.

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

References (127)

  • E.S. Schelegle et al.

    Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae)

    Am J Pathol

    (2001)
  • E.S. Schelegle et al.

    Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys

    Toxicol Appl Pharmacol

    (2003)
  • H.G. Johnson et al.

    Inhibition of the 5-lipoxygenase pathway with piriprost (U-60, 257) protects normal primates from ozone-induced methacholine hyperresponsive small airways

    Prostaglandins

    (1988)
  • M.J. Evans et al.

    Fibroblast growth factor-2 in remodeling of the developing basement membrane zone in the trachea of infant rhesus monkeys sensitized and challenged with allergen

    Lab Invest

    (2002)
  • J.C. Hogg

    The pathology of asthma

    Clin Chest Med

    (1984)
  • E.H.I. Adachi et al.

    Basement-membrane stromal relationships: interactions between collagen fibrils and the lamina densa

    Inter Rev Cytol

    (1997)
  • M. Hoshino et al.

    Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogen immunoreactivity in asthmatic airways and its relationship to angiogenesis

    J Allergy Clin Immunol

    (2001)
  • E.R.J. McFadden

    Exercise-induced asthma as a vascular phenomenon

    Lancet

    (1990)
  • M.J. Evans et al.

    The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit

    Am J Respir Cell Mol Biol

    (1999)
  • L.S. Van Winkle et al.

    Maintenance of differentiated murine clara cells in microdissected airway cultures

    Am J Respir Cell Mol Biol

    (1996)
  • L.S. Van Winkle et al.

    Repair of naphthalene-injured microdissected airways in vitro

    Am J Respir Cell Mol Biol

    (1996)
  • K.E. Pinkerton et al.

    Tracheobronchial airways

    Comprehens Toxicol

    (1997)
  • C.G. Plopper et al.
  • C.G. Plopper et al.

    Postnatal changes in the expression and distribution of pulmonary cytochrome P450 monooxygenases during clara cell differentiation in the rabbit

    Mol Pharmacol

    (1993)
  • A.T. Mariassy
  • D.M. Hyde et al.

    Ozone-induced acute Tracheobronchial epithelial injury: relationship to granulocyte emigration in the lung

    Am J Respir Cell Molec Biol

    (1992)
  • C.G. Plopper et al.

    Relationship of inhaled ozone concentration to acute tracheobronchial epithelial injury, site-specific ozone dose, and glutathione depletion in rhesus monkeys

    Am J Respir Cell Mol Biol

    (1998)
  • C. Plopper et al.

    Relationship of cytochrome P-450 activity to Clara cell cytotoxicity: I histopathologic comparison of the respiratory tract of mice, rats and hamsters after parenteral administration of naphthalene

    J Pharmacol Exp Ther

    (1992)
  • C. Plopper et al.

    Relationship of cytochrome P-450 activity to clara cell cytotoxicity III. Morphometric comparison of changes in the epithelial populations of terminal bronchioles and lobar bronchi in mice, hamsters, and rats after parenteral administration of naphthalene

    Lab Invest

    (1992)
  • L.A. Miller et al.

    Airway generation-specific differences in the spatial distribution of immune cells and cytokines in allergen-challenged rhesus monkeys

    Clin Exp Allergy

    (2005)
  • C. Plopper et al.

    Differentiation of tracheal epithelium during fetal lung maturation in the rhesus monkey, macaca mulatta

    Am J Anat

    (1986)
  • C.G. Plopper et al.

    Tracheal submucosal gland development in the rhesus monkey, macaca mulatta: Ultrastructure and histochemistry

    Anat Embryol

    (1986)
  • U. Bucher et al.

    Development of the mucus-secreting elements in human lung

    Thorax

    (1961)
  • M.J. Evans et al.

    Fibroblast growth factor-2 during postnatal development of the tracheal basement membrane zone

    Am J Physiol Lung Cell Mol Physiol

    (2002)
  • C.E. Brewster et al.

    Myofibroblasts and subepithelial fibrosis in bronchial asthma

    Am J Respir Cell Molec Biol

    (1990)
  • C. Gaultier et al.

    Normal and pathological lung growth: structure–function relationships

    Bull Eur Physiopathol Respir

    (1980)
  • A.A. Hislop et al.

    Airway size and structure in the normal fetal and infant lung and the effect of premature delivery and artificial ventilation

    Am Rev Respir Disease

    (1989)
  • M.U. Tran et al.

    Smooth muscle development during postnatal growth of distal bronchioles in infant rhesus monkeys

    J Appl Physiol

    (2004)
  • M.U. Tran et al.

    Smooth muscle hypertrophy in distal airways of sensitized infant rhesus monkeys exposed to house dust mite allergen

    Clin Exp Allergy

    (2004)
  • F.B. Daniel et al.

    Interspecies comparisons of benzo(a)pyrene metabolism and DNA-adduct formation in cultured human and animal bladder and tracheobronchial tissues

    Cancer Res

    (1983)
  • C. Lee et al.

    Site-selective differences in cytochrome P450 isoform activities. Comparison of expression in rat and rhesus monkey lung and induction in rats

    Drug Metab Dispos

    (1998)
  • S.K. Krueger et al.

    Drug Metab Dispos

    (2001)
  • H.K. Choi et al.

    A comparative study of mammalian tracheal mucous glands

    J Anat

    (2000)
  • J.G. Heidsiek et al.

    Quantitative histochemistry of mucosubstance in tracheal epithelium of the macaque monkey

    J Histochem Cytochem

    (1987)
  • C.G. Plopper et al.

    Tracheobronchial epithelium in the adult rhesus monkey: a quantitative histochemical and ultrastructural study

    Am J Anat

    (1989)
  • J.A. St. George et al.

    An immunohistochemical characterization of rhesus monkey respiratory secretions using monoclonal antibodies

    Am Rev Respir Disease

    (1985)
  • J.A. St. George et al.

    Carbohydrate cytochemistry of rhesus monkey tracheal submucosal glands

    Anat Rec

    (1986)
  • J.A. St. George et al.

    Carbohydrate cytochemistry of the rhesus monkey tracheal epithelium

    Anat Rec

    (1984)
  • F. Dupuit et al.

    Expression and localization of CFTR in the rhesus monkey surface airway epithelium

    Gene Ther

    (1995)
  • H. Huang et al.

    Changes in epithelial secretory cells and potentiation of neurogenic inflammation in the trachea of rats with respiratory tract infections

    Anat Embryol

    (1989)
  • Cited by (81)

    • Choice of the non-human primate for biomedical research

      2023, Spontaneous Pathology of the Laboratory Non-human Primate
    • Contemporary Formulation Development for Inhaled Pharmaceuticals

      2021, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Non-human primates such as monkeys have been assessed as an animal model for COPD and asthma. The structural components of their airways – e.g. smooth muscles, cartilage and submucosal glands – are more similar to humans than other animal models.159 Monkeys have been used to study local alveolar deposition and delivery of antibodies after aerosolised delivery into lungs.160

    • Tracheobronchial Airways

      2018, Comprehensive Toxicology: Third Edition
    • Osteoprotegerin mediate RANK/RANKL signaling inhibition eases asthma inflammatory reaction by affecting the survival and function of dendritic cells

      2019, Allergologia et Immunopathologia
      Citation Excerpt :

      Asthma has different characteristics in different patients, ranging in severity from mild and occasional symptoms to severe and persistent effects on daily life.24 Asthma models have been established in a variety of animals using a variety of methods, with supporters in each animal model – rats,25 dogs,26 rabbits,27 guinea pigs,28 sheep29 and primates.30 However, the most commonly used standard animal model is the OVA-induced mouse asthma model.31

    View all citing articles on Scopus
    View full text