Pathophysiology and Treatment of Inhalation Injuries

J. Loke

• Editorial: CRC Press
• Año: 2020
• ISBN:
  9781000147001
• Edición: 1
• Categoría: Medicine
• Categoría: Medical Theory, Practice & Reference

This book covers several aspects of inhalation toxicology ranging from inhalation drug abuse to battlefield chemical inhalation lung injury, and emphasizes pathophysiology and therapy.

1 Airway Repair and Adaptation to Inhalation Injury

S. F. PAUL MAN and WILLIAM C. HULBERT
University of Alberta
Edmonton, Alberta, Canada

There is a continuum of epithelial injuries due to the inhalation of noxious gases and fumes that exist in our environment today; the exposure extremes vary between acute massive and chronic low level. A massive exposure is usually the result of an accident, industrial or otherwise; often there are systemic effects in addition to severe injury to the lungs and eyes, and there is significant morbidity and mortality. Two recent examples of this level of exposure were the sodium cyanate exposure in Bhopal, India, where a large population was at risk, and the Lodgepole sour gas well blow out (of which hydrogen sulfide was a major component) in Alberta, Canada, where a few individuals were injured. These incidences are significant because they were industrial accidents, are potentially preventable, and invariably occur in or near populated areas.

At the other extreme of the spectrum is chronic low-level exposure to a large number of man-made noxious gases. Such low-level exposures, although unavoidable in our civilization, have only recently been recognized as serious health hazards. The total number of noxious gases in the environment and at the work site is increasing; the more common ones are the photochemical oxidants, oxygenated organic compounds such as the oxides of nitrogen and sulfur, ozone, and many others derived from fuel combustion. In contrast to the acute massive exposure, the pathologic changes in the airway following chronic low-level exposure are more subtle and at times difficult to assess. Whereas it is clear that massive acute exposures are life threatening, chronic low-level exposures are less so, indeed, the complex question regarding risk factors or a safety limit of exposure is only now being addressed and demands answers.

The epithelial repair processes following massive or low concentration exposures are different because the lesions caused by these different levels of exposure differ in severity. Adaptation to inhaled oxidant gases is, by definition, exclusively restricted to low-concentration, chronic exposures; as will be discussed later, the development of adaptation is not without a price. Unified concepts of the adaptative and repair processes are still evolving and, in most situations, the steps of these processes, though similar, are dependent upon a multitude of interacting factors.

In this chapter we will review data obtained primarily from animal experiments regarding the injury, repair, and adaptative processes following the inhalation of some of the more common oxidizing gases other than oxygen itself: sulfur dioxide (SO₂, an example of the sulfur oxides), nitrogen dioxide (NO₂, an example of the nitrogen oxides), and ozone (O₃).

I. Organization of the Airway Epithelium

In order to understand the processes of repair and adaptation, it is necessary to review briefly the structural organization of the airway epithelium and to define the function of the cellular constituents. The respiratory tract extends from the external nares to the respiratory bronchioles and at the level of the larynx is arbitrarily divided into the upper and lower tracts. The upper respiratory tract is connected to the paranasal sinuses, the eustachian tubes, and the mastoids. The lower tract is a series of conducting tubes whose branching pattern varies from species to species. The upper and the lower respiratory tracts are covered by a continuous layer of epithelium whose cellular composition changes in the transition from the nares to the peripheral respiratory bronchioles. As anticipated, functional changes of the airway epithelium are related to the cellular changes.

The morphology and population dynamics of the cells lining the nasal passages, the conducting airways, and the gas exchange units have been extensively studied and reviewed (Jeffery and Reid, 1977; Plopper, 1983; Plopper et al., 1980a,b,c, 1983; Gail and Lenfant, 1983). Although interspecies differences in the cellular composition of the respiratory tract epithelium are noted, some generalizations can be drawn. In the upper airway, except for parts of the anterior nares where it is squamous, the epithelium is mostly ciliated, columnar, and pseudostratified. On scanning electron microscopy (SEM), in the trachea and in the mainstem and lobar bronchi the epithelium appears as a dense ciliary mat because of the large surface area of the ciliated cells relative to the other superficial cell types. In the airways peripheral to the lobar bronchi, the epithelium becomes thinned to a single cell layer, the proportion of nonciliated to ciliated cells increases, and, in contrast to the ciliary mat seen in the trachea, on SEM the protruding apex of the nonciliated Clara cell is seen projecting into the bronchiolar lumen (Fig. 1).

Jeffery and Reid (1977) classified the cells in the airway epithelium into subgroups on the basis of their location within the mucosa, the presence of cilia, and the presence or type of secretory granules; a modification of their schema is shown in Figure 2. At least 10 cell types, 8 of them epithelial, are now recognized as resident mucosal cells although not all are present in every species. The distribution of these cells in the central airways has been found to vary between species although the number of ciliated vs. nonciliated cells that communicate with the airway lumen is fairly constant, comprising between 40 and 60% of the cell population (Plopper et al., 1980a,b,c). As shown in Figure 2, the nonciliated superficial cells (those that communicate with the airway lumen) are made up of two different populations: secretory and nonsecretory. Both cell classes have been studied extensively and it is well established that the ultrastructural characteristics of the two populations of nonciliated cells vary markedly between species, within an individual animal, and can change following exposure to irritant gases.

Several investigators (Spicer et al., 1971; Jones and Reid, 1973; Spicer et al., 1980;Plopper et al., 1984; St. George et al., 1985), using classic histochemical methods, lectins immunospecific for sugar residues on proteoglycans, and monoclonal antibodies, have examined the biochemical nature of secretory products within cells in the respiratory epithelium. As a result of these studies, three classes of secretory cells are generally recognized: mucous cells, serous cells, and Clara cells.

The Clara cell is perhaps the most extensively studied nonciliated superficial cell in the airway mucosa (Clara, 1937; Kuhn et al., 1974; Kuhn, 1976; Plopper et al., 1980a,b,c, 1983; Plopper, 1983; Young et al., 1986). This cell, as originally described by Max Clara, had unique ultrastructural characteristics. It was a cuboidal nonciliated cell in the bronchioles, the cellular apex of which projected into the airway lumen. Also, it was filled with dense granules. Recent studies (Plopper et al., 1980a,b,c; Plopper, 1983), however, showed that the ultrastructural features of this cell type vary considerably between species. For example, in the mouse, guinea pig, rat, hamster, and rabbit, there is an abundance of agranular endoplasmic reticulum (AER). The AER has been shown to have high levels of cytochrome p-450 monooxygenase activity and is postulated to be associated with the synthesis of secretory material and the detoxification of xenobiotic compounds. In other species, such as humans and primates,

Figure 1 An SEM view of the surface of a bronchus from a guinea pig shows the protruding apices of the abundant nonciliated bronchiolar (Clara) cells and the ciliated cells. The marker bar represents 10 μm. The inset is a light micrograph of a bronchiolar cross-section showing the thick band of smooth muscle underlying the one-cell-layer-thick epithelium. In this view are examples of internalized bronchiolar circulation that causes the ridged appearance of the surface view. The marker bar represents 20 μm.

Figure 2 This schema is a modification of one published earlier (Jeffery and Reid, 1977) to illustrate the different residuent cell types in the tracheal mucosa. The Kulchitsky cell is also a superficial cell in the guinea pig.

the cells do not have abundant AER. The electron-dense granules in humans, the hamster, guinea pig, and rabbit stain positive for the vicinal hydroxyl group (or PAS-positive) whereas the granules in the mouse stain positive for phospholipid. The Clara cells in the cat do not contain granules. In addition, in most species examined, the Clara cells differ in their structural features depending upon the airway generation in which they are present, whereas in the mouse and rabbit they are the same throughout the airways.

A more recent study (Young et al., 1986) has shed some light on the heterogeneity of Clara cell structure. These investigators evaluated rat bronchus using three-dimensional reconstruction. Their findings suggest that some of the reported variability in Clara cell structure is due to the organelles not being randomly distributed throughout the cytoplasm. They found that within the same cell it was possible to obtain cross-sectional images characterized by a lack of mitochondria and numerous granules, or numerous mitochondria and no granules. Moreover, these same authors also found that the electron density of the granules varied from light to dense core within the same cell, had a polarized distribution, and yet exhibited cytochemical characteristics that were similar. Although these same investigators have perhaps identified a source of confusion over the variability in reports on Clara cell ultrastructure, they support previous findings (Plopper et al., 1980a,b,c) that considerable variability in the morphological characteristics exists between species. The role of the Clara cell in the detoxification of inhaled compounds and its contribution to the airway lining layer remains speculative and not well understood. However, it has been suggested that they are capable of synthesis and secretion of protein, carbohydrate, and possibly cholesterol (Widdicombe and Park, 1982). By contrast, the role of the Clara cell as a progenitor cell with an ability to redifferentiate into goblet or ciliated cells following exposure to inhaled irritants such as SO₂ (Lamb and Reid, 1968), NO₂ and O₃ (Evans et al., 1976; Lum et al., 1978), or cigarette smoke (Wells and Lamerton, 1975) has been well established.

The other two secretory cell types, the mucous or goblet and serous cells, are present in both the mucosal epithelium and the submucosal glands. The term goblet cell was originally applied to the mucous cells as a descriptive term to denote the cell shape when they are engorged with secretory granules. There are important differences between the mucous and serous cells in the structure of their granules, the secretory process, their stimulation by various neural and humoral factors, and their distribution in the sub...