Chronic smoke exposure alters the phenotype pattern and the metabolic response in human alveolar macrophages

Sköld, C. Magnus; Lundahl, Joachim; Halldén, Gunilla; Hallgren, M.; Eklúnd, Anders

doi:10.1046/j.1365-2249.1996.d01-805.x

Cited by 62 publications

(48 citation statements)

References 25 publications

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“…A similar difference could not be found in smokers' macrophages. Hypothetically, this divergence could be attributed to the generally lower expression of CD54 in smokers' sputum or BAL material shown in this study as well as in other reports [22]. However, that hypothesis should, then, also be true for other markers expressed differently by smokers and nonsmokers macrophages.…”

Section: Discussionsupporting

confidence: 59%

Leukocyte counts and macrophage phenotypes in induced sputum and bronchoalveolar lavage fluid from normal subjects

Lensmar¹,

Elmberger²,

P³

et al. 1998

Eur Respir J

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Bronchoalveolar lavage (BAL) is a well-standardized method for retrieving cells and soluble material from the lung. An alternative, less invasive method to recover such material is induced sputum (IS). The method provides an opportunity to perform frequent observations, in order to follow a dynamic course of pulmonary inflammatory disease and effects of treatment. Recent research on IS has focused on markers of inflammation in asthma and the method has, in that context, proven to be reliable, for instance in the evaluation of airway eosinophilia [1][2][3][4][5][6][7][8][9].There is still, however, a need to determine the degree of correlation between IS and BAL material and to establish baseline values for IS variables in healthy individuals. The main difference between the processing of IS and BAL is the incubation of sputum material with a disulphide reducing agent, dithiothreitol (DTT), which is carried out to obtain cell dispersion [10]. Incubation of samples with DTT allows a high repeatability in differential cell counts, but has been shown to interfere with immunological detection of some cellular antigens, for example, the intracellular expression of eosinophil cationic protein, EG2 [10].The most predominant cell in the alveolar and airway lining fluid is the macrophage. Studies of material recruited from the airways and alveoli separately [11] have implied the presence of morphologically different subsets of macrophages deriving from different levels of the bronchoalveolar tree.The present study was conducted to determine intraindividual differences in cell-count data and macrophage phenotypes in IS and BAL collected from healthy smokers and nonsmokers and to investigate any measurable DTTmediated effect on macrophage immunocytochemical staining results. Materials and methods SubjectsIS and BAL fluid samples were collected from 16 subjects; nine smokers, six females and three males, mean age 27.9 yrs (range 21-38) and seven nonsmokers, five females and two males, mean age 26.6 yrs (range 19-38). The smokers mean cigarette consumption was 10.4±7.2 pack-yrs (mean±SD), and present consumption exceeded 10 cigarettes·day -1 for the last 5 yrs.All subjects had normal pulmonary radiographs and showed no clinical signs of respiratory disease. IS samples BAL and IS samples were processed and cell viability and cell counts were assessed. The macrophages were characterized by seven monoclonal antibodies (RFD1, RFD7, CD11b, CD54, CD68, CD71 and HLA-DR) using an indirect immunoalkaline phosphatase method.Intraindividual comparison of IS and BAL showed that IS samples from smokers and nonsmokers contained a lower total cell count (p<0.0l smokers, p<0.05 nonsmokers), a lower percentage of macrophages (both p<0.05) and a higher percentage of neutrophils (both p<0.05) than BAL samples. In addition, nonsmokers sputum samples contained a lower proportion of lymphocytes (p<0.05) than BAL. The macrophage expression of RFD7 and CD71 was higher in smokers sputum samples (both p<0.05) than in BAL, while nonsmokers sputum macro...

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Section: Discussionsupporting

confidence: 59%

Leukocyte counts and macrophage phenotypes in induced sputum and bronchoalveolar lavage fluid from normal subjects

Lensmar¹,

Elmberger²,

P³

et al. 1998

Eur Respir J

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“…Of these, CR3, CD14, CD31, CD36, CD44, LRP, vitronectin receptor, and the phosphatidylserine receptor have been previously observed to be expressed on human AMs (24,(49)(50)(51)(52), and MERTK has been noted to be expressed on cultured blood monocytes, the cells from which AMs are derived (5). In the present study, expression by MERTK by AMs was observed by microarray, TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow cytometry.…”

Section: Expression Of Mertk On Amsmentioning

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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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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“…Cigarette smokers exhibit reduced SP-D levels (43), elevated MMP levels (44), and reduced alveolar macrophage CD14 levels (45). In addition, human alveolar macrophages in culture produced significantly less TNF-␣ and IL-6 after cigarette smoke exposure (46).…”

Section: Macrophages From Cd14mentioning

confidence: 99%

Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12

Senft¹,

Korfhagen²,

Whitsett³

et al. 2005

The Journal of Immunology

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Surfactant protein D (SP-D) and CD14 are important innate immune defense molecules that mediate clearance of pathogens and apoptotic cells from the lung. To test whether CD14 expression and function were influenced by SP-D, the surface expression of CD14 was assessed on alveolar macrophages from SP-D−/− mice. CD14 was reduced on alveolar macrophages from SP-D−/− mice and was associated with reduced uptake of LPS and decreased production of TNF-α after LPS stimulation. CD14 is proteolytically cleaved from the cell surface to form a soluble peptide. Soluble CD14 (sCD14) was increased in the bronchoalveolar lavage fluid from SP-D−/− mice. Because matrix metalloproteinase (MMP)-9 and -12 activities were increased in the lungs of SP-D−/− mice, the role of these metalloproteases in the production of sCD14 was assessed. sCD14 was decreased in both MMP9−/−/SP-D−/− and MMP12−/−/SP-D−/− mice demonstrating MMP-9 and MMP-12 contribute to proteolytic shedding of CD14. The increased sCD14 seen in SP-D−/− mice was dependent upon the activation of MMP-12 via an MMP-9-dependent mechanism. Supporting this observation, MMP-12 caused the release of sCD14 from RAW 264.7 cells in vitro. In conclusion, SP-D influences innate host defense, in part, by regulating sCD14 in a process mediated by MMP-9 and MMP-12.

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Chronic smoke exposure alters the phenotype pattern and the metabolic response in human alveolar macrophages

Cited by 62 publications

References 25 publications

Leukocyte counts and macrophage phenotypes in induced sputum and bronchoalveolar lavage fluid from normal subjects

Leukocyte counts and macrophage phenotypes in induced sputum and bronchoalveolar lavage fluid from normal subjects

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

Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12

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