Correlation of lung surface area to apoptosis and proliferation in human emphysema

Imai, Kazushi; Mercer, Becky A.; Schulman, Larry L.; Sonett, Joshua R.; DʼArmiento, Jeanine

doi:10.1183/09031936.05.00023704

Cited by 197 publications

(175 citation statements)

References 25 publications

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“…The present study demonstrates that MERTK, an apoptotic cell surface removal receptor (3,5,44,45), is expressed on normal human AMs, and the expression of MERTK is markedly up-regulated on AMs of normal cigarette smokers, as demonstrated by mRNA analysis by microarray and TaqMan RT-PCR, and protein analysis with immunocytochemistry, Western analysis, and flow cytometry. In the context that smoking is associated with increased pulmonary cell turnover, the finding that expression of MERTK is up-regulated in normal smokers may reflect an attempt to enhance clearance of apoptotic cells in the lung burdened with the stress of smoking (17,18,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

“…In the context that there is more cell turnover in smokers and individuals with COPD (25)(26)(27)(28)(29)(30)(31)(32)(33)(34), the observation that MERTK is up-regulated and functional in the AMs of smokers may reflect several important findings. It may reflect not only an increased demand for removal of apoptotic cells but also an effort to compensate for the lack of up-regulation or dysfunction of other apoptotic cell removal receptors which would ultimately decrease the inflammatory burden in the lungs of smokers.…”

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confidence: 99%

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Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Kazeros

Harvey²,

Carolan³

et al. 2008

Am J Respir Cell Mol Biol

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Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AMs) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AMs obtained by bronchoalveolar lavage of normal nonsmokers (n 5 11) and phenotypic normal smokers (n 5 13; 36 6 6 pack-years) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER tyrosine kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AMs of smokers versus nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow analysis. Smoker AMs had up-regulation of MERTK mRNA levels (smoker vs. nonsmoker: 3.6-fold by microarray, P , 0.003; 9.5-fold by TaqMan RT-PCR, P , 0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AMs of smokers. Increased protein expression of MERTK on AMs of smokers was confirmed by Western and flow analyses (P , 0.007 and P , 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers. This up-regulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.Keywords: apoptosis; MER tyrosine kinase; alveolar macrophages MER receptor tyrosine kinase (MERTK), a 110-kD transmembrane protein member of the receptor tyrosine kinase family of cell surface receptors, plays a role in the clearance of apoptotic cells (1-4). The MERTK gene is normally expressed on mononuclear phagocytes, dendritic cells, retinal pigment epithelial (RPE) cells, and reproductive tissue (5-8). In mice, deletion of MERTK results in delayed clearance of apoptotic cells and development of autoimmune disease (1, 9, 10). In humans, mutations in MERTK result in retinitis pigmentosa, a disease characterized by a defect in the RPE phagocytosis pathway, where the RPE cells are unable to ingest the shed apoptotic tips of photoreceptor cells (11)(12)(13)(14).In the lung, the clearance of apoptotic cells is the normal function of alveolar macrophages (AMs), the monocyte-derived pulmonary representative of the mononuclear phagocyte system (15-18). Because phagocytosis of apoptotic cells by mononuclear phagocytes invokes an array of receptors on the phagocyte that interacts with bridging molecules and cell-specific ligands on the apoptotic cells, the control of expression of apoptotic receptors on the phagocyte plays ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Kazeros

Harvey²,

Carolan³

et al. 2008

Am J Respir Cell Mol Biol

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“…In this line, recent data from animal (Sawada et al 2007, Rangasamy et al 2009) and human studies suggest an imbalance between apoptosis and the repair of structural cells in the lung, favoring the destruction of lung tissue in response to cigarette smoke, which would lead to emphysema. Smoke exposure interferes with cell proliferation, chemotaxis, and production/remodeling of matrix components by fibroblasts (Carnevali et al 1998, Rennard et al 2006, which partially explains the increased number of apoptotic cells in human lungs with severe emphysema (Yokohori et al 2004, Imai et al 2005. In COPD, apoptotic cells include alveolar and bronchial epithelial cells, as well as endothelial cells in the parenchyma.…”

Section: Elastase Vs Smoke-induced Emphysemamentioning

confidence: 99%

Elastase-induced pulmonary emphysema: insights from experimental models

Antunes

Rocco

2011

An. Acad. Bras. Ciênc.

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Several distinct stimuli can be used to reproduce histological and functional features of human emphysema, a leading cause of disability and death. Since cigarette smoke is the main cause of emphysema in humans, experimental researches have attempted to reproduce this situation. However, this is an expensive and cumbersome method of emphysema induction, and simpler, more efficacious alternatives have been sought. Among these approaches, elastolytic enzymes have been widely used to reproduce some characteristics of human cigarette smoke-induced disease, such as: augmentation of airspaces, inflammatory cell influx into the lungs, and systemic inflammation. Nevertheless, the use of elastase-induced emphysema models is still controversial, since the disease pathways involved in elastase induction may differ from those occurring in smoke-induced emphysema. This indicates that the choice of an emphysema model may impact the results of new therapies or drugs being tested. The aim of this review is to compare the mechanisms of disease induction in smoke and elastase emphysema models, to describe the differences among various elastase models, and to establish the advantages and disadvantages of elastase-induced emphysema models. More studies are required to shed light on the mechanisms of elastase-induced emphysema.

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“…For example, several animal models of COPD are associated with increased accumulation (58 -61) and impaired removal (45) of apoptotic cells. Likewise, apoptotic cells are increased in COPD lungs (31,(62)(63)(64)(65) and efferocytosis is defective in COPD alveolar macrophages ex vivo (32). Therefore, we tested the effect of lovastatin on efferocytosis by alveolar macrophages isolated from GOLD stage 2 (66) COPD patients (Table I).…”

Section: Lovastatin Enhances Efferocytosis By Human Alveolar Macrophamentioning

confidence: 99%

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

Morimoto

Janssen²,

Fessler³

et al. 2006

The Journal of Immunology

198

179

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Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.

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Correlation of lung surface area to apoptosis and proliferation in human emphysema

Cited by 197 publications

References 25 publications

Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette Smokers

Elastase-induced pulmonary emphysema: insights from experimental models

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

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