Apoptosis and the airway epithelium

Abstract

The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases.

Figure 1

Extrinsic (receptor-mediated) and intrinsic (stress or oxidant-mediated) pathways that initiate apoptosis. Receptors such as CD95 and DR4 initiate apoptosis by interacting with death domain proteins such as FADD or TRADD, leading to the cleavage and activation of procaspase-8 with subsequent activation of downstream caspases and the initiation of the nuclear and cytoplasmic events that comprise apoptosis. In the intrinsic pathway, stress or oxidant-mediated injury leads to activation of proapoptotic BH3 proteins such as BAX or BAK; these then induce disruption of mitochondrial polarity leading to the release of cytochrome c, which binds APAF-1 in the “apoptosome,” leading to cleavage and activation of caspase-9. This then leads to downstream caspase activation. Cross-talk from the extrinsic pathway via the truncation of Bid (to t-Bid) can also elicit disruptions of mitochondrial polarity so that both pathways may be activated. Mitochondrial integrity is regulated by a series of related antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bad, Bax, Bak) proteins. The downstream caspase cascade can be inhibited by inhibitors of apoptosis such as XIAP, cIAP-1, and cIAP-2.

Figure 2

Expression of the CD95 receptor (a) and its ligand, CD95L (b), in a normal human airway using an immunoperoxidase method. Both basal and columnar cells stain for receptor and ligand (brown, with hematoxylin counter label). The appropriate controls (not shown here) for substitution of primary antibody do not label. Original magnification, 200x. From [20].

Figure 3

Demonstration of apoptotic airway epithelial cells, as demonstrated by TUNEL stain for single-strand DNA nicking using a peroxidase method (brown, with hematoxylin counter label), in an endobronchial biopsy of a normal subject (a) and of a subject with chronic, persistent asthma (b). Note the substantial difference in the height of the epithelium and the gaps in the epithelium at the basement membrane between the two biopsies, and the loss of ciliated cells in asthmatic biopsy. The appropriate controls (not shown here) do not label. Original magnification, 200x. From the author's laboratory.