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Discovering inflammatory biomarkers in chronic obstructive pulmonary disease and cystic fibrosis : a case study of granzyme B

University of British Columbia

Granzymes, and particularly granzyme B (GzmB), are classically known to be involved in cell-mediated immunity and the induction of apoptosis through cell-specific targeting activity of cytotoxic T-lymphocytes in conjunction with perforin. However, recent literature has emerged that describes a largely overlooked role for GzmB in potentially mediating disease progression. This pathogenic role has been based on findings that GzmB can cleave extracellular matrix proteins while functioning independently of perforin. In chronic inflammatory lung states such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), there are important implications including the degradation of extracellular matrix leading to airway remodelling, reduced lung integrity, and emphysema. The generation of autoantigens may also result from cleavage of extracellular matrix proteins, contributing to inflammation. We measured GzmB levels in plasma and lung tissue homogenates of COPD subjects by enzyme-linked immunosorbent assays (ELISAs) to determine the relationship with lung function, measured by FEV₁% predicted and FEV₁/FVC ratio, and clinical COPD severity. We found that GzmB levels in the lung were positively associated with lung function. The data raise the possibility that the GzmB we measured may be part of a protective inflammatory response in the microenvironment, or it may be pathogenic in the early but not the later phases of COPD. In CF subjects, we measured levels of GzmB and other inflammatory biomarkers in plasma samples to determine their relationship with lung function parameters and hospitalization status. While plasma levels of GzmB were not related to lung function or hospitalization status, we found that IL-6, IL-1β, and LPS levels were significantly higher in hospitalized patients, and CRP, IL-6, IL-1β, and LBP were significantly correlated with lung function impairment. The results provide evidence that systemic inflammation is an independent factor associated with disease progression in CF and suggests an important role for chronic bacterial colonization in the lungs. Further research is needed to validate the pathogenic contributions of GzmB in diseases with chronic inflammatory lung states and to delineate the mechanisms of such potential contributions.

Text

2011-07-25

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/36292

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/