Apoptotic mechanisms in the pathogenesis of COPD

Figures & data

Table 1 Studies of apoptosis in COPD

Cell type		Reference
Epithelial and endothelial cells
Human studies	↑apoptosis	Segura-Valdez (2000); Majo (2001)
	↓ VEGF, ↓ VEGF R2, ↓ VEGF KDR ↑ bax	Kasahara, Tuder, Cool (2000); Kasahara et al (2001)
	sFRP-1 gene expression	Yokohori (2004); Imai et al (2005)
	↑ bad	Imai and D’Armiento (2002)
	↑ Fas	Imai et al (2005)
	↑ p53	Hodge et al (2005)
	↑ activated caspases	Hodge et al (2005)
	↑ 4-HNE-modified proteins	Hodge et al (2005) Rahman et al (2002)
Animal and in vitro studies	VEGF R blockade → ↑ apoptosis injection of caspase 3 or Chariot → ↑ apoptosis	Kasahara, Tuder, Taraseviciene-Stewart, et al (2000); Tuder, Zhen, et al (2003)
	PIGF transgenic mice → ↑ apoptosis, ↓ VEGF	Aoshiba et al (2003)
	↓ ingestion of apoptotic cells by macrophages	Tsao et al (2004) Hodge, Hodge, Scicchitano, et al (2003)
Neutrophils
Human and animal studies	No difference in PBN apoptosis in stable COPD	Pletz et al (2004); Noguera et al (2004)
	↓ PBN apoptosis in acute exacerbations	Pletz et al (2004)
	↑ Mac-1, ↓ L-selectin of PBN	Noguera et al (2004)
	apoptosis of BALF granulocytes (horses)	Turlej et al (2001)
Lymphocytes
Human studies	↑apoptosis, ↑Fas, ↑TNF-a, ↑TNFR1, ↓bcl2 in PBT	Hodge, Hodge, Reynolds, et al (2003); Hodge et al (2005)
	↑ apoptosis, ↑p53, ↑ activated caspases in BALFT	Hodge et al (2005)
Skeletal myocytes
Human studies	No difference in apoptosis between COPD-controls	Gosker et al (2003)
	↓ apoptosis in COPD with low BMI	Agusti et al (2002)
Soluble apoptotic markers
Human studies	↑ plasma sFas in severe COPD	Yasuda et al (1998)
	No difference in plasma sFasL	Yasuda et al (1998); Takabatake et al (2000)

Abbreviations: BALF, bronchoalveolar lavage fluid; BALFT, BALF T-cells; BMI, body mass index; sFRP-1, frizzled-related protein; 4-HNE, 4-Hydroxy-2-nonenal; KDR, kinase insert domain-containing receptor; PBN, peripheral blood neutrophils; PBT, peripheral blood T-cells; PIGF, placenta growth factor; R, receptor; sFas, soluble Fas receptor; sFasL; soluble Fas ligand; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Table 2 Markers upregulating (↑) or downregulating (↓) apoptosis in COPD

Apoptotic markers	Apoptosis
bcl-2	↓
bax	↑
bad	↑
Akt	↓
TNF-α	↑
Fas–Fas ligand	↑
p53	↑
4-Hydroxy-2-nonenal	↑
sFRP-1	↑

Abbreviations: sFRP-1, frizzled-related protein; TNF-α, tumor necrosis factor-α.

Figure 1 Lung epithelial cell apoptosis. Increased apoptosis of epithelial cells may account for the decreased vascular endothelial growth factor (VEGF) expression, resulting in alveolar endothelial cells death. The compromised microcirculation resulting from endothelial cell damage may further promote pneumocyte cell death. Increased elastolytic activity in apoptotic lung epithelial cells amplifies the destruction of alveolar elastin. The subsequent destruction of the basement membrane and the loss of cell–extracellular matrix attachments lead to further apoptosis of the surrounding cells.

Abbreviations: BM, basement membrane; ECM, extracellular matrix.

Figure 2 Oxidative stress of cigarette smoke in “susceptible” smokers activates adaptive immunity, predisposing dendritic cells to clonal expansion of CD4 + and especially of cytotoxic CD8 + cells, inducing epithelial cell death by perforin.

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