Upregulation of Gelatinases A and B, Collagenases 1 and 2, and Increased Parenchymal Cell Death in COPD

Segura-Valdez, Lourdes; Pardo, Annie; Gaxiola, Miguel; Uhal, Bruce D.; Becerril, Carina; Selman, Moisés

doi:10.1378/chest.117.3.684

Cited by 446 publications

(343 citation statements)

References 33 publications

Supporting

Mentioning

319

Contrasting

Unclassified

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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 ...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…This abnormal remodelling results in a net increase in deposited ECM and collagen content in lungs, resulting from MMPs/TIMPs imbalance (Jeffery 2001). These lung disorders are also characterized by a striking fibroblast/myofibroblast proliferation and activation, which increase the production of matrix-degrading enzymes (Crouch 1990, Segura-Valdez et al 2000. Furthermore, local over-expression of cytokines and/or growth factor stimulates resident lung fibroblasts to synthesize increased amount of collagen and different MMPs such as collagenase-1 (MMP-1), gelatinases A and B (MMP-2 and MMP-9) (Sasaki et al 2000, Zhu et al 2001.…”

Section: Therapeutical Potential Of Selective Pde4 Inhibitorsmentioning

confidence: 99%

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

Lagente

Martin-Chouly

Boichot

et al. 2005

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

Phosphodiesterases (PDEs) The selective targeting of phosphodiesterases type 4 (PDE4) has been actively pursued as a novel therapeutic approach in the treatment of respiratory diseases associated with inflammatory processes such as asthma and chronic obstructive pulmonary disease (COPD). The rationale for their use in respiratory disease is based on the clinical efficacy of non-selective PDE inhibitors such as theophylline, the detection of PDE4 in many of the cells involved in these diseases and the emergence of positive results from a number of pharmacological studies and clinical trials currently evaluating the efficacy of selective PDE4 inhibitors in respiratory diseases (Barnette 1999, Spina 2000. PDE4 represent the major class of PDE expressed in human inflammatory cells (Wang et al. 1999) and in particular in macrophages, eosinophils and neutrophils, the main cell types present in the lungs of asthmatic and COPD patients.PDE4 are members of the phosphodiesterase (PDE) superfamily of enzymes, which comprises at least 11 members hydrolyzing cyclic AMP (adenosine 3',5'-cyclic monophosphate) and/or cyclic GMP (guanosine 3',5'-cyclic monophosphate) (Houslay et al. 1998, Conti & Jin 1999, Giembycz 2000. In the case of PDE4, there are four gene products and multiple splice variants resulting in a variety of PDE4 isoforms. PDE4 selectively catalyse the hydrolysis of cAMP and the anti-inflammatory effects of selective PDE4 inhibitors were supposed to result of the reduction of cAMP hydrolysis. However, some recent studies have demonstrated that PDE4 could also act through cAMP-independent mechanisms. Indeed, we have observed that PDE4 inhibitors triggered a cAMP-independent inhibition of fMLP-induced O 2. -release from bronchoalveolar lavage cells of rats exposed to lipopolysaccharide . We also showed that the inhibitory effect of PDE4 inhibitors on O 2. -production is mediated by the activation of p44/42 MAPK and that PDE4 inhibit p44/42 MAPK by a direct interaction ). This study allowed us to identify a novel mechanism involving MAPK in the pathway connecting PDE4 to fMLP-induced O 2. -generation in neutrophils.

show abstract

“…Cigarette smoking stimulates recruitment of inflammatory cells, cell death, and protease production (2)(3)(4)(5)(6). Chronic obstructive pulmonary disease pathology includes small airway inflammation, destruction of airway parenchyma (7), and elevated protease expression (8,9). However, the intracellular signaling mechanisms activated by tobacco smoke that mediate the protease/antiprotease imbalance and subsequent matrix degradation in the lungs are not well understood.…”

mentioning

confidence: 99%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

View full text Add to dashboard Cite

The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

show abstract

Upregulation of Gelatinases A and B, Collagenases 1 and 2, and Increased Parenchymal Cell Death in COPD

Cited by 446 publications

References 33 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

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Contact Info

Product

Resources

About