Alveolar epithelial and endothelial cell apoptosis in emphysema: what we know and what we need to know

Abstract

Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space. However, mechanisms involved in its development are not fully understood. Alveolar cell apoptosis has been previously investigated in the lung of emphysematous subjects as a potential contributor to the loss of alveolar cell and has been found abnormally elevated. Though, mechanisms involved in the increased alveolar apoptosis that occurs in emphysema have now become a prolific field of research. Those mechanisms are reviewed here with special focus on how they affect cell viability and how they may be implicated in emphysema. Moreover, we suggest a model that integrates all those mechanisms to explain the increased alveolar apoptosis observed in emphysema. This review also includes some reflections and suggestions on the research to come.

Figure 1

Apoptosis pathways. Abbreviations: cFLIP, cellular FLICE-like inhibitory protein; FADD, Fas-associated death domain; FasL, Fas ligand; TNF, tumor necrosis factor; TRAIL,TNF-related apoptosis-inducing ligand; TRAIL-R, TRAIL receptor; Rock, Rho kinase; AIF, apoptosis-inducing factor; PUMA, p53 upregulated modulator of apoptosis; NOXA, damage.

Figure 2

Mechanisms by which leucocyte elastase (LE), neutrophil elastase (NE), and proteinase 3 (PR3) may induce alveolar epithelial and endothelial cell apoptosis. α-1 antitrypsin (A1AT), proteinase activated receptor 1 (PAR-1), matrix metalloproteinase (MMP), tissue inhibitor of matrix metalloproteinase (TIMP), extracellular-signal regulated kinase (ERK).

Figure 3

Cigarette smoke (oxidative stress)-mediated VEGF signaling disruption leading to endothelial cell death, migration impairment, and general endothelium dysfunction causing epithelial cells apoptosis. Abbreviation: VEGF, vascular endothelial growth factor.

Figure 4

Increased alveolar apoptosis mediated through oxidative stress-induced cellular damages.

Figure 5

Sensitization to TRAIL-mediated apoptosis. Abbreviation: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TRAIL-R, TRAIL receptors.

Figure 6

Induction of an autoimmune response against immunogenic self-antigens after protease and oxidative stress-induced modifications. Antigen-presenting cell (APC). Self-antigen (▪), modified self-antigen (⬢), antibody against modified self-antigen (Y).

Figure 7

Proposed model of the mechanisms involved in the increased alveolar apoptosis observed in emphysema (see text for details).