Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with defective efferocytosis (apoptosis and alveolar macrophage [AM] phagocytic function) that may lead to secondary necrosis and tissue damage. We investigated ex vivo AM phagocytic ability and recognition molecules (CD36, integrin alphaVbeta3, CD31, CD91, CD44) using flow cytometry. The transferrin receptor (CD71) was measured as an indicator of monocyte-macrophage differentiation in bronchoalveolar lavage (BAL). Proliferation was assessed with Ki-67. Based on evidence of systemic involvement in COPD, blood from 17 current smokers and 25 ex-smokers with COPD, 22 healthy smokers, and 20 never-smoking control subjects was also investigated. BAL was collected from 10 to 16 subjects in each group. Levels of recognition molecules and cAMP were assessed after exposure of AM to cigarette smoke in vitro. The phagocytic ability of AM was significantly decreased in both COPD groups and in healthy smokers compared with control subjects. However, phagocytic capacity was better in subjects with COPD who had ceased smoking, compared with those who were still smoking. AM from current smokers with COPD and healthy smokers exhibited reduced CD31, CD91, CD44, and CD71, and enhanced Ki-67 compared with healthy never-smoker control subjects. There were no differences in these markers in AM from ex-smokers with COPD compared with control subjects, or in blood monocytes from any group. Suppressive effects of cigarette smoke on AM recognition molecules associated with an increase in cAMP were confirmed in vitro. Our data indicates that a smoking-related reduction in AM phagocytic ability and expression of several important recognition molecules may be at least partially normalized in those subjects with COPD who have ceased smoking.

[1]  J. Lundahl,et al.  Chronic smoke exposure alters the phenotype pattern and the metabolic response in human alveolar macrophages , 1996, Clinical and experimental immunology.

[2]  S. Hodge,et al.  Increased Airway Granzyme b and Perforin in Current and Ex-Smoking COPD Subjects , 2006, COPD.

[3]  E. Wouters,et al.  Enhanced levels of hyaluronan in lungs of patients with COPD: relationship with lung function and local inflammation , 2005, Thorax.

[4]  G. Hodge,et al.  Phenotypic analysis of functional T‐lymphocyte subtypes and natural killer cells in human cord blood: relevance to umbilical cord blood transplantation , 1995, British journal of haematology.

[5]  C. Sköld,et al.  Different inflammatory cell pattern and macrophage phenotype in chronic obstructive pulmonary disease patients, smokers and non‐smokers , 2006, Clinical and experimental immunology.

[6]  L. Koenderman,et al.  Systemic inflammation in chronic obstructive pulmonary disease , 2003, European Respiratory Journal.

[7]  S. Hodge,et al.  Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation , 2005, European Respiratory Journal.

[8]  Yunchao Su,et al.  Effect of cigarette smoke extract on nitric oxide synthase in pulmonary artery endothelial cells. , 1998, American journal of respiratory cell and molecular biology.

[9]  C. Haslett,et al.  CD44 regulates phagocytosis of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human macrophages. , 1997, Journal of immunology.

[10]  R. Pauwels,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. , 2001, Respiratory care.

[11]  John Savill,et al.  Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment , 2002, Nature.

[12]  P. Rakic,et al.  Phosphatidylserine Receptor Is Required for Clearance of Apoptotic Cells , 2003, Science.

[13]  W. Seeger,et al.  Phenotypic characterization of alveolar monocyte recruitment in acute respiratory distress syndrome. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[14]  S. Hodge,et al.  Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages , 2006, European Respiratory Journal.

[15]  E. Puré,et al.  Resolution of Lung Inflammation by CD44 , 2002, Science.

[16]  P. Barnes,et al.  Alveolar macrophages in chronic obstructive pulmonary disease (COPD). , 2004, Cellular and molecular biology.

[17]  S. Hodge,et al.  Flow cytometric characterization of cell populations in bronchoalveolar lavage and bronchial brushings from patients with chronic obstructive pulmonary disease , 2004, Cytometry. Part B, Clinical cytometry.

[18]  C. Haslett,et al.  Regulation of macrophage phagocytosis of apoptotic cells by cAMP. , 1998, Journal of immunology.

[19]  S. Hodge,et al.  Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells , 2003, Immunology and cell biology.

[20]  D. Aronoff,et al.  Cutting Edge: Macrophage Inhibition by Cyclic AMP (cAMP): Differential Roles of Protein Kinase A and Exchange Protein Directly Activated by cAMP-11 , 2005, The Journal of Immunology.

[21]  I. Rahman,et al.  Macrophage phagocytosis of apoptotic neutrophils is compromised by matrix proteins modified by cigarette smoke and lipid peroxidation products. , 2004, Biochemical and biophysical research communications.

[22]  R. Baughman,et al.  Report of ERS Task Force: guidelines for measurement of acellular components and standardization of BAL. , 1999, The European respiratory journal.

[23]  H. Magnussen,et al.  Alveolar macrophages from bronchoalveolar lavage of patients with pulmonary histiocytosis X: Determination of phenotypic and functional changes , 2004, Lung.

[24]  J Savill,et al.  Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. , 1992, The Journal of clinical investigation.

[25]  A. Agustí,et al.  Phenotypic characterisation of alveolar macrophages and peripheral blood monocytes in COPD , 2005, European Respiratory Journal.

[26]  I. Douglas,et al.  Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. , 2006, Chest.

[27]  V. Fadok,et al.  Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. , 1992, Journal of immunology.

[28]  J. Nick,et al.  By Binding SIRPα or Calreticulin/CD91, Lung Collectins Act as Dual Function Surveillance Molecules to Suppress or Enhance Inflammation , 2003, Cell.