Elsevier

Toxicology

Volume 160, Issues 1–3, 7 March 2001, Pages 173-180
Toxicology

Factors modulating the epithelial response to toxicants in tracheobronchial airways

https://doi.org/10.1016/S0300-483X(00)00453-4Get rights and content

Abstract

As one of the principal interfaces between the organism and the environment, the respiratory system is a target for a wide variety of toxicants and carcinogens. The cellular and architectural complexity of the respiratory system appears to play a major role in defining the focal nature of the pulmonary response to environmental stressors. This review will address the biological factors that modulate the response of one of the major target compartments within the respiratory system, the tracheobronchial airway tree. Individual airway segments respond uniquely to toxic stress and this response involves not only the target cell population, e.g. epithelium, but also other components of the airway wall suggesting a trophic interaction within all components of the airway wall in maintaining steady state and responding to injury. A number of biological factors modulate the nature of the response, including: (1) metabolic potential at specific sites for activation and detoxification; (2) the nature of the local inflammatory response; (3) age of the organism at the time of exposure; (4) gender of the exposed organism; (5) history of previous exposure; and (6) species and strain of the organism exposed.

Introduction

The respiratory system is exposed to a wide variety of environmental contaminants. The cellular and architectural complexity of this system establishes a wide range of microenvironments with different cellular composition and response to environmental stressors. The variable nature of the response is consistent regardless of whether the route of exposure is via inhaled air or the vascular system. More than 40 cell phenotypes found in the lungs are not uniform either in their distribution throughout the organ or in their response to toxicants. This is especially true for target cell populations that occupy the tracheobronchial airway tree. Increasing evidence strongly suggests that cell populations within the tracheobronchial airways establish distinct microenvironments that vary markedly in their steady state biological activity and in their potential for response to environmental stressors. The composition of the entire airway wall appears to contribute to the steady state function of all of the cell populations within the local environment. In addition, all the cell populations appear to respond to stress even when only one subpopulation is targeted. This discussion will first address the concept of the organization of an airway wall as a microenvironment of complex cellular and acellular composition with strong trophic interactions. In addition, the current state of our understanding of the biological factors, which modulate the response of these individual microenvironments as targets of toxic injury, will be defined.

Section snippets

Epithelial–mesenchymal trophic unit as a paradigm

The concept of the epithelial–mesenchymal trophic unit was developed as a framework for defining the cellular and metabolic mechanisms regulating the response to toxic injury in a complex biological structure such as the tracheobronchial airway tree (Evans et al., 1999, Holgate, 2000). Each segment, or airway generation, within the branching pattern is addressed as a unique biological entity whose properties may differ from those of neighboring branches. The portions of the airways between

Modulating factors

Using the concept that the cellular population which organizes a conducting airway as a biological entity unique to a particular branch of the airway tree emphasizes the number of factors by which they differ in their pathobiological response to toxic injury, including susceptibility to acute injury, the pattern of repair and the development of tolerance. Issues to be considered include: airway microenvironment, the status of differentiation based on animal age, the history of previous exposure

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