Granzyme B deficiency exacerbates lung inflammation in mice after acute lung injury.

TitleGranzyme B deficiency exacerbates lung inflammation in mice after acute lung injury.
Publication TypeJournal Article
Year of Publication2013
AuthorsHirota, JA, Hiebert, PR, Gold, M, Wu, D, Graydon, C, Smith, JAnn, Ask, K, McNagny, K, Granville, DJ, Knight, DA
JournalAm J Respir Cell Mol Biol
Volume49
Issue3
Pagination453-62
Date Published2013 Sep
ISSN1535-4989
KeywordsAcute Lung Injury, Administration, Intranasal, Animals, Antigens, CD, Bleomycin, Case-Control Studies, Forkhead Transcription Factors, Gene Expression, Granzymes, Humans, Killer Cells, Natural, Lung, Mice, Mice, Knockout, Pneumonia, Respiratory Distress Syndrome, Adult, Survival Analysis, T-Lymphocytes, Regulatory
Abstract

Granzyme B (GzmB) is a serine protease with intracellular and extracellular activities capable of regulating inflammation through cytokine processing and the apoptosis of effector cells. We tested the hypothesis that GzmB expression in T regulatory cells (Tregs) is required for the control of inflammatory responses and pathology during acute lung injury. To substantiate the clinical relevance of GzmB during lung injury, we performed GzmB immunohistochemistry on lung tissue from patients with acute respiratory distress syndrome (ARDS) and healthy control subjects. We also performed in vivo experiments with wild-type (WT) C57BL/6 and GzmB(-/-) mice exposed to a single intranasal instillation of bleomycin to model lung injury. Our results demonstrate that the expression of GzmB was elevated in ARDS lung sections, relative to healthy control samples. Bleomycin-exposed GzmB(-/-) mice exhibited greater morbidity and mortality, which was associated with increased numbers of lung lymphocytes. Bleomycin induced an equal increase in CD4(+)/CD25(+)/FoxP3(+) Treg populations in WT and GzmB(-/-) mice. GzmB expression was not significant in Tregs, with the majority of the expression localized to natural killer (NK)-1.1(+) cells. The expression of GzmB in NK cells of bleomycin-exposed WT mice was associated with greater lymphocyte apoptosis, reduced total lymphocyte numbers, and reduced pathology relative to GzmB(-/-) mice. Our data demonstrate that GzmB deficiency results in the exacerbation of lymphocytic inflammation during bleomycin-induced acute lung injury, which is associated with pathology, morbidity, and mortality.

DOI10.1165/rcmb.2012-0512OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID23642129
Grant List2012-04-01 / / Canadian Institutes of Health Research / Canada