Increased airway granzyme b and perforin in current and ex-smoking COPD subjects.
Increased bronchial epithelial cell apoptosis and CD8+ T-cell numbers in the blood and airways have been reported in COPD. These cells can induce apoptosis via the granzyme-b/perforin-mediated pathway. We hypothesized that increased levels of granzyme-b/perforin would be detected in COPD, contributing to apoptosis and tissue damage. Intracellular granzyme-b/perforin were measured in blood-derived T-cells and natural killer (NK) cells from COPD subjects (30 current and 30 ex-smokers), 20 asymptomatic current-smokers and 30 never-smokers, and bronchoalveolar lavage (BAL)-derived T-cells from a cohort of these subjects using flow cytometry. Soluble granzyme-b was determined by ELISA. In blood, there was an increased percentage of T-cells expressing intracellular granzyme-b/perforin for both COPD groups but not asymptomatic smokers (versus never-smokers). Soluble granzyme-b was undetectable. In BAL, soluble granzyme-b levels and the percentage of T-cells expressing intracellular granzyme-b/perforin were increased in both COPD groups and asymptomatic smokers. There was a significant correlation between granzyme-b expression in BAL and apoptosis of bronchial epithelial cells. Most circulating NK cells expressed granzyme-b/perforin, with the median fluorescence intensity of staining increased in both COPD groups and asymptomatic smokers. Granzyme-mediated apoptosis may thus be one mechanism of lung injury in COPD. The changes that persist despite smoking cessation in COPD likely reflect pathophysiological changes in COPD as opposed to the effects of smoking per se.
Hodge
Sandra
S
Department of Thoracic Medicine, Royal Adelaide Hospital and Lung Research Laboratory, Hanson Institute, Adelaide, South Australia. sandy.hodge@imvs.sa.gov.au
Hodge
Greg
G
Nairn
Judith
J
Holmes
Mark
M
Reynolds
Paul N
PN
D000328:Adult; D000368:Aged; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D011379:Prognosis; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D012907:Smoking; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes