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

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Abstract

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.

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