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

Figures & data

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.

Table 1 Characteristics of studies reporting elevated apoptosis in the emphysematous lung

Authors	Studied group	Control group	Apoptosis detection technique	Apoptotic cell type
Segura-Valdez et al 2000^Citation22	Smokers with emphysema	Smokers and nonsmokers without COPD	In situ end labeling	Mainly endothelial cells
Kasahara et al 2000^Citation40	Smokers with emphysema	Smokers and nonsmokers without emphysema	DNA fragmentation (TUNEL and LM-PCR) Single DNA detection (IHC)	Epithelial and endothelial cells
Yokohori et al 2004^Citation11	Subjects with emphysema (smoking state not specified)	Smokers and nonsmokers without emphysema	DNA fragmentation (TUNEL)	Epithelial cells (mainly type II alveolar cells)
Calabrese et al 2005^Citation97	Subjects with AAT-deficiency emphysema	Young subjects with unspecified smoking history	DNA fragmentation (TUNEL and agarose gel separation)	Alveolar wall cells
Imai et al 2005^Citation10	Ex-smokers (>6 months) with emphysema	Nonsmokers with unspecified lung functions	cleaved caspase-3 and PARP (Western blot) and DNA fragmentation (agarose gel separation)	Not mentionned

Abbreviations: COPD, chronic obstructive pulmonary disease; IHC, immunohistochemistry; LM-PCR, ligation-mediated polymerase chain reaction; PARP, poly(ADP-ribose) polymerase; TUNEL, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling.

Table 2 Animal models used to study apoptosis in emphysema

Authors	Model of emphysema	Apoptosis detection technique	Apoptotic cell type
Kasahara et al 2000^Citation40	Subcutaneaous injection of a VEGF receptor blocker (Sprague-Dawley rats)	DNA fragmentation (TUNEL and LM-PCR) Active caspase-3 (IHC)	Alveolar epithelial and endothelial cells
Lucey et al 2002^Citation27	Intratracheal instillation of porcine pancreatic elastase (B6129SF2/J mice)	DNA fragmentation (TUNEL)	Alveolar epithelial cells
Aoshiba et al 2003^Citation98	Single intratracheal delivery of caspase-3 (C57BL/6 mice)	DNA fragmentation (TUNEL) and ssDNA detection (IHC)	Mainly alveolar epithelial cells
Bartalesi et al 2005^Citation99	Whole-body exposure to cigarette smoke (C57BL/6 and DBA/2 mice)	DNA fragmentation (TUNEL)	General increase but unspecified cell type
Kuo et al 2005^Citation100	Whole-body exposure to cigarette smoke (Wistar rats)	DNA fragmentation (TUNEL)	General increase but unspecified cell type
Zheng et al 2005^Citation28	Transgenic lung IFN-γ overexpression (CC10-rtTA-IFN-γ mice)	DNA fragmentation (TUNEL)	Mainly alveolar Type I and Type II cells
Petrache et al 2005^Citation101	Single intratracheal delivery of C12ceramide (C57BL/6 mice)	DNA fragmentation (TUNEL)	Mainly endothelial cells but also Type II alveolar epithelial cells
Taraseviciene-Stewart et al 2005^Citation85	Anti-endothelial cells immunization that triggered autoimmune response (Sprague-Dawley rats)	DNA fragmentation (TUNEL) and active caspase-3 (IHC)	Alveolar epithelial cells
Brass et al 2008^Citation102	Exposure to lipopolysaccharide (C57BL/6 mice)	DNA fragmentation (TUNEL) and active caspase-3 (Western blot)	Alveolar epithelial cells

Abbreviations: IFN, interferon; IHC, immunohistochemistry; LM-PCR, ligation-mediated polymerase chain reaction; TUNEL, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling; VEGF, vascular endothelial growth factor.

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).

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