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Increased Granzyme A Expression in Type II Pneumocytes of Patients with Severe Chronic Obstructive Pulmonary Disease

¹ Nutrition and Toxicology Research Institute Maastricht, Department of Respiratory Medicine and ² Department of Pathology, University Hospital Maastricht, Maastricht, The Netherlands; ³ Department of Anatomy and Embryology, Maastricht University, Maastricht, The Netherlands; ⁴ Laboratory of Pneumology, Unit Lung Toxicology, K.U. Leuven, Leuven, Belgium; and ⁵ Centrum voor Integrale Revalidatie Orgaanfalen Horn, Horn, The Netherlands

Correspondence and requests for reprints should be addressed to Juanita H. J. Vernooy, Ph.D., Department of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: j.vernooy{at}pul.unimaas.nl

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased numbers of CD8⁺ cytotoxic T lymphocytes (CTLs) in the lung, but the functional activity of CTLs remains unknown. Granzyme A (GrA) and B (GrB) are serine proteases considered to be important effector molecules of CTLs and natural killer cells.

Objective: To investigate protein and mRNA expression of GrA and GrB in peripheral lung tissue from patients with COPD and control subjects with normal lung function.

Methods: Paraffin-embedded sections of surgical lung specimens from 22 patients with COPD (FEV₁, 22% predicted; GOLD stage 4) and 15 control subjects (FEV₁, 108% predicted) were immunostained for GrA and GrB, and semiquantified on a 3-point scale. Messenger RNA expression in total lung, specific cell types enriched for by laser capture microdissection, and freshly isolated primary cells were determined by reverse transcriptase–polymerase chain reaction.

Measurements and Main Results: GrA and GrB immunoreactivity was observed in CD8⁺ CTLs and CD57⁺ natural killer cells, but also in type II pneumocytes and alveolar macrophages in both groups. Bronchiolar epithelium stained positive for GrA, but negative for GrB. These observations were confirmed by reverse transcriptase–polymerase chain reaction on total lung, laser capture microdissection–enriched specific cell types and freshly isolated primary type II pneumocytes. The scores of GrA-expressing type II pneumocytes were significantly higher in patients with COPD versus control subjects.

Conclusions: GrA and GrB mRNA and protein are detectable in human lung tissue. GrA expression is increased in type II pneumocytes of patients with very severe COPD. These results indicate that GrA may be important in the development of COPD.

Key Words: CD8⁺ cytotoxic T lymphocyte • immunohistochemistry • laser capture microdissection • serine proteases • type II pneumocytes

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The significant correlation between the number of CD8+ cytotoxic T lymphocytes and the degree of airflow limitation in COPD indicates a role of these cells in the progression of COPD, but the mechanism by which lymphocytes contribute to the pathogenesis of COPD is unknown. What This Study Adds to the Field Granzyme A expression is increased in type II pneumocytes of patients with severe COPD and may be important in the development of this disease.

 

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