State of the Art. Apoptosis and Cell Homeostasis in Chronic Obstructive Pulmonary Disease

Abstract

Examination of lung tissue from patients with chronic obstructive pulmonary disease (COPD) reveals the presence of apoptotic cells (1–3). This raises two key questions: What induces the apoptosis and how important is it for pathogenesis of the disease? However, before considering these questions, it is important to emphasize that the Kasahara and colleagues' study (1) used a variety of approaches to show that the cells they were identifying had indeed undergone the process of apoptosis. This does not exclude additional ongoing direct cell damage and necrosis, or postapoptotic necrosis, but does focus attention specifically on apoptosis and its consequences. As noted below, in normal circumstances, apoptotic cells are rapidly removed in situ with minimal local tissue response, a process with a time frame of minutes, not hours, days, or years. Accordingly, the consistent presence of apoptotic cells either means constant induction of apoptosis on a very wide scale or, more likely, defective clearance mechanisms. This then leads us to the third series of questions focusing on the nature of the defective clearance as well as its own contribution to pathogenesis. Normally, apoptotic cells are rapidly removed from tissues as a component of cellular homeostasis. In fact, programmed cell death (whether of apoptotic or autophagocytic origins) may be considered primarily as a mechanism for cell removal, with an emphasis on removal. We have suggested that this clearance process is normally so efficient that the finding of detectable apoptotic cells in a tissue could reasonably raise the possibility of defects in the clearance mechanisms (4, 5) (see below). A striking experiment that supports this contention is that induction of total apoptosis of murine thymocytes results in essentially invisible removal unless the mice are defective in one or more apoptotic clearance systems (6). In humans, clearance of apoptotic neutrophils during acute community-acquired pneumonia is almost invisible (< 1% detectable apoptosis [7]) compared with cystic fibrosis where we showed evidence of defective clearance (8). Defective clearance may be implicated in lesions of atherosclerosis where statin treatment led to deceased presence of apoptotic cells (9). Apoptotic cell removal occurs by a unique form of phagocytosis (termed “efferocytosis”) (10, 11), which can be carried out by structural tissue cells, such as fibroblasts, epithelial cells, and endothelial cells, as well as by professional phagocytes, such as macrophages and dendritic cells. However, as noted below, this ingestion of apoptotic cells is only one manifestation of their recognition by surrounding cells, which also includes generation of antiinflammatory mediators, antiproteases, and growth/maintenance factors (Figure 1). These last, we suggest, contribute to replacement of the damaged cells and to the return of normal tissue structure and function (i.e., maintenance of homeostasis). These concepts have set the stage for the hypothesis to be discussed herein, namely that, in COPD, defects in maintenance of cellular homeostasis and of normal responses to apoptosis or damaged cells lead to loss of alveolar structure and of total alveolar numbers (i.e., emphysema; Figure 1). Figure 1. Model for the normal response to apoptotic cells in the alveolus compared to an impaired response proposed for chronic obstructive pulmonary disease (COPD). HGF = hepatocyte growth factor; TGF-β = transforming growth factor β; ...