Functional Significance of Apoptosis in Chronic Obstructive Pulmonary Disease

Park, Jeong-Woong; Ryter, Stefan W.; Choi, Augustine M.K.

doi:10.1080/15412550701603775

Cited by 78 publications

(70 citation statements)

References 56 publications

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“…A-aDO 2 should be increased proportionally by the reduced surface and integrity of AECs. Recently, injury of AECs has been of great concern as the primary pathogenesis of smoking-induced PE (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)31,35,36). A recent ultrastructural study showed early disruption of AECs to be associated with smoking-induced chronic inflammatory processes and regional hypoxia (1,3,31).…”

Section: Rgbmentioning

confidence: 99%

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Impaired Lung ¹²³I-MIBG Uptake on SPECT in Pulmonary Emphysema

Suga¹,

Okada

Kunihiro

et al. 2011

J Nucl Med

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The aim of this study was to evaluate impaired lung uptake of 123 I-metaiodobenzylguanidine ( 123 I-MIBG) on SPECT, compared with perfusion SPECT and morphologic CT, in patients with pulmonary emphysema (PE). Methods: 123 I-MIBG SPECT was performed at 15 min and 4 h after intravenous injection of 123 I-MIBG in 36 PE patients with a history of smoking and variable-extent low-attenuation areas on CT, indicative of emphysematous changes, and in 16 controls with no history of smoking and no noticeable low-attenuation areas. The distribution of 123 I-MIBG was compared with that of low-attenuation areas on CT and perfusion on SPECT at the base of the 180 lung lobes of the PE patients. Total-lung 123 I-MIBG kinetics were calculated, including early and delayed lung-to-mediastinum uptake ratios and washout rate. Results: The controls showed a fairly uniform lung 123 I-MIBG distribution nearly consistent with perfusion. PE patients had heterogeneous 123 I-MIBG defects showing frequent discordance with low-attenuation areas or perfusion distribution; 123 I-MIBG defects were more extensive than low-attenuation areas in 76 lobes (42.2%) of 31 patients (86%) and more extensive than perfusion defects in 44 lobes (24.4%) of 22 patients (61%). 123 I-MIBG defects were seen regardless of the absence of noticeable low-attenuation areas and perfusion defects in 19 lobes (10.5%) of 16 patients (44%). All total-lung 123 I-MIBG kinetic parameters in PE patients were significantly lower than the control values (P , 0.0001), with significant correlation with alveolar-arterial oxygen tension gradient but without correlation with the extent of perfusion defects or low-attenuation areas. Conclusion: 123 I-MIBG SPECT allows evaluation of lung pathophysiology in PE independently of perfusion SPECT or morphologic CT, and impairment of lung 123 I-MIBG uptake may be more extensive than perfusion or morphologic abnormalities in PE.

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Section: Rgbmentioning

confidence: 99%

“…Injury of alveolar endothelial cells (AECs) is of great concern and has been considered the primary pathogenesis of PE (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Several histopathologic studies have shown early damage of these cells in smokers and mild-PE patients (2)(3)(4)(8)(9)(10).…”

mentioning

confidence: 99%

Impaired Lung ¹²³I-MIBG Uptake on SPECT in Pulmonary Emphysema

Suga¹,

Okada

Kunihiro

et al. 2011

J Nucl Med

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“…Over the past decades, inflammation and a protease/antiprotease imbalance have been the focus of studies that addressed lung destruction following chronic cigarette smoking. More recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism contributing to the development of lung emphysema, accounting for the unique nature of lung destruction as compared with that with other inflammatory lung diseases (1)(2)(3). The identification of molecular mediators that trigger and integrate lung responses involving inflammation and alveolar cell apoptosis in response to cigarette smoke (CS) exposure offers the potential for development of novel therapies.…”

Section: Introductionmentioning

confidence: 99%

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

et al. 2011

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Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPII resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPII expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and exsmoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.

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“…Because ceramide is a second messenger molecule that modulates cell apoptosis (13)(14)(15)(16)(17)(18) and oxidative stress (16), others and we have proposed that ceramide upregulation may induce lung epithelial destruction, as presented in the pathogenesis of several lung injury diseases (3,16,19). Recent reports provide a very strong case for cell death (apoptosis) having a major role in lung injury in several pulmonary diseases, such as asthma, bronchitis, and COPD (1,3,5,(20)(21)(22). In simple terms, loss of cells by augmented apoptosis would be expected to be involved, or perhaps initiate, the overall tissue destruction responsible for lung injury (21,22).…”

mentioning

confidence: 99%

Neutral Sphingomyelinase 2

Filosto

Castillo

Danielson³

et al. 2011

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is caused by exposure to cigarette smoke (CS). One mechanism of CS-induced lung injury is aberrant generation of ceramide, which leads to elevated apoptosis of epithelial and endothelial cells in the alveolar spaces. Recently, we discovered that CS-induced ceramide generation and apoptosis in pulmonary cells is governed by neutral sphingomyelinase (nSMase) 2. In the current experiments, we expanded our studies to investigate whether nSMase2 governs ceramide generation and apoptosis in vivo using rodent and human models of CSinduced lung injury. We found that exposure of mice or rats to CS leads to colocalizing elevations of ceramide levels and terminal deoxynucleotidyl transferase mediated X-dUTP nick end labelingpositive cells in lung tissues. These increases are nSMase2 dependent, and are abrogated by treatment with N-acetyl cysteine or antinSMase2 small interfering RNA (siRNA). We further showed that mice that are heterozygous for nSMase2 demonstrate significant decrease in ceramide generation after CS exposure, whereas acidic sphingomyelinase (aSMase) knockout mice maintain wild-type ceramide levels, confirming our previous findings (in human airway epithelial cells) that only nSMase2, and not aSMase, is activated by CS exposure. Lastly, we found that lung tissues from patients with emphysema (smokers) display significantly higher levels of nSMase2 expression compared with lung tissues from healthy control subjects. Taken together, these data establish the central in vivo role of nSMase2 in ceramide generation, aberrant apoptosis, and lung injury under CS exposure, underscoring its promise as a novel target for the prevention of CS-induced airspace destruction.

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Functional Significance of Apoptosis in Chronic Obstructive Pulmonary Disease

Cited by 78 publications

References 56 publications

Impaired Lung ¹²³I-MIBG Uptake on SPECT in Pulmonary Emphysema

Impaired Lung ¹²³I-MIBG Uptake on SPECT in Pulmonary Emphysema

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

Neutral Sphingomyelinase 2

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Functional Significance of Apoptosis in Chronic Obstructive Pulmonary Disease

Cited by 78 publications

References 56 publications

Impaired Lung 123I-MIBG Uptake on SPECT in Pulmonary Emphysema

Impaired Lung 123I-MIBG Uptake on SPECT in Pulmonary Emphysema

Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke–induced emphysema in mice

Neutral Sphingomyelinase 2

Contact Info

Product

Resources

About

Impaired Lung ¹²³I-MIBG Uptake on SPECT in Pulmonary Emphysema

Impaired Lung ¹²³I-MIBG Uptake on SPECT in Pulmonary Emphysema