Repair mechanisms in asthma,☆☆,

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Abstract

Asthma is classically defined in terms of reversible airflow obstruction. It is now recognized that histologic abnormalities, including inflammation, are a regular feature of asthma. In addition, alterations of the structural elements of the airway wall occur regularly in asthma. These alterations include a thickened basal lamina comprised of interstitial collagens as well as alterations in the mesenchymal cell population with an accumulation of myofibroblasts. It seems likely that these connective tissue alterations in the airway wall contribute to the physiologic abnormalities of asthma. While controversial, the long-term physiologic sequela of asthma may depend in large part on these changes. The biochemical and cellular basis that leads to these changes is, as yet, unknown, but recent studies suggest that a variety of cells in the airway, including inflammatory cells and the cells of the airway epithelium, may participate in regulating this response. (J ALLERGY Clin Immunol 1996;98:278-86.)

Section snippets

NORMAL EPITHELIUM

The normal airway epithelium (Fig. 1A) is lined by a complex layer of epithelial cells.77, 78 In the proximal airways it is pseudostratified, meaning that all cells are believed to have contact with the basement membrane, although several layers of nuclei may be present. Most of the basement membrane surface is covered by basal cells, which anchor the epithelium via hemidesmosomes.79 The majority of cells that reach the airway lumen are ciliated cells, although smaller numbers of secretory

EPITHELIAL INJURY IN ASTHMA

Epithelial injury regularly occurs in asthma and can result in desquamation of epithelial cells (Fig. 1B). Frequently sheets of columnar cells are detached as aggregates, resulting in the formation of creola bodies.13 The epithelial defect can alter airway function in asthma by a variety of mechanisms.78, 81, 82 First, the epithelial barrier is disrupted, permitting both ready absorption of environmental agents and leakage of plasma components into the airway lumen. Airway nerves also may

RESPONSE OF THE EPITHELIUM TO INJURY

Injury of the epithelium initiates a complex cascade of responses (Fig. 1C). Epithelial cells are activated to release a variety of mediators, including TGF-β and fibronectin, which can serve to recruit and activate both neighboring epithelial cells and subjacent mesenchymal cells. Epithelial cells also can release a variety of mediators that can recruit and activate inflammatory cells (not shown in Fig. 1C) and can, moreover, respond to mediators released by inflammatory cells.78, 83, 84 The

REPAIR WITH ALTERED ARCHITECTURE

Repair of the airway epithelium does not necessarily restore the epithelial architecture to normal (Fig. 1D). The normal ciliated epithelial cells can be replaced by goblet cells or even squamous cells (not shown in Fig. 1D). In addition, increased numbers of mesenchymal cells can accumulate in the subepithelial layer together with the connective tissue matrix produced by these cells. It is likely that these cells are responsible for the thickened lamina reticularis that characterizes asthma.10

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    From the University of Nebraska Medical Center.

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    Reprint requests: Stephen I. Rennard, MD, University of Nebraska Medical Center, Pulmonary and Critical Care Medicine Section, 600 South 42 Street, Omaha, Nebraska 68198-5300.

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