Increased p21(CIP1/WAF1) and B cell lymphoma leukemia-x(L) expression and reduced apoptosis in alveolar macrophages from smokers.
Alveolar macrophages (AMs) are the predominant defense cells in the airway, and their numbers are increased in smokers and subjects with chronic obstructive pulmonary disease. This increase may result from increased recruitment, increased proliferation, or reduced cell death. Apoptosis regulates inflammatory cell survival, and p21(CIP1/WAF1) is an important inhibitory regulator of cycle progression after oxidative stress. We have investigated whether chronic smoke exposure influences the expression and localization of cell cycle and apoptotic proteins in AM and bronchial epithelial cells in vivo. The increased numbers of AMs seen in smokers were only partially due to enhanced proliferation. p21(CIP1/WAF1) protein expression was increased in AMs and biopsies isolated from smokers and was found predominantly within the cytoplasm. In addition, B cell lymphoma leukemia (Bcl)-x(L), an antiapoptotic regulator, was also highly expressed in macrophages from smokers compared with nonsmokers and subjects with asthma. Hydrogen peroxide, an oxidative stress, induced cytoplasmic expression of p21(CIP1/WAF1) and failed to induce apoptosis in an in vitro model. These results suggested that AM and bronchial epithelial cells from smokers, in contrast to those from normal subjects and subjects with asthma, have reduced cell death. Thus, oxidative stress induced by cigarette smoking may contribute to the chronicity of inflammation in the airway, through a reduction of apoptosis.
Department of Thoracic Medicine, National Heart and Lung Institute at Imperial College School of Science, Technology and Medicine, London, United Kingdom.
Katsuyuki
K
Tomita
Gaetano
G
Caramori
Sam
S
Lim
Kazuhiro
K
Ito
Toyoyuki
T
Hanazawa
Timothy
T
Oates
Irena
I
Chiselita
Elen
E
Jazrawi
K Fan
KF
Chung
Peter J
PJ
Barnes
Ian M
IM
Adcock
D000328:Adult; D017209:Apoptosis; D001249:Asthma / Q000473:pathology*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001999:Bronchoscopy; D016022:Case-Control Studies; D002455:Cell Division; D002478:Cells, Cultured; D002908:Chronic Disease; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000235:genetics; D016676:Macrophages, Alveolar / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D012907:Smoking / Q000473:pathology*; D018709:Statistics, Nonparametric; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein