title: Granzyme B deficiency exacerbates lung inflammation in mice after acute lung injury.
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.
authors: University of British Columbia James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC, Canada. jeremy.hirota@hli.ubc.ca
authors: Jeremy A
authors: JA
authors: Hirota
authors: Paul R
authors: PR
authors: Hiebert
authors: Matt
authors: M
authors: Gold
authors: Dan
authors: D
authors: Wu
authors: Colin
authors: C
authors: Graydon
authors: Jane Ann
authors: JA
authors: Smith
authors: Kjetil
authors: K
authors: Ask
authors: Kelly
authors: K
authors: McNagny
authors: David J
authors: DJ
authors: Granville
authors: Darryl A
authors: DA
authors: Knight
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology* / Q000401:mortality; D000281:Administration, Intranasal; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001761:Bleomycin; D016022:Case-Control Studies; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology* / Q000401:mortality; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology / Q000473:pathology
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D001761:Bleomycin; D053804:Granzymes