Autor: |
Murphy MP; Department of Medicine, Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland., Zieger M; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States.; Department of Ophthalmology, Tufts Medical Center, Center for Translational Ocular Immunology, Boston, Massachusetts, United States., Henry M; National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland., Meleady P; National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland., Mueller C; Genomic Medicine Unit, Sanofi, Waltham, Massachusetts, United States., McElvaney NG; Department of Medicine, Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland., Reeves EP; Department of Anaesthesia and Critical Care Medicine, Pulmonary Clinical Science, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. |
Abstrakt: |
Elastin is an extracellular matrix protein (ECM) that supports elasticity of the lung, and in patients with chronic obstructive pulmonary disease (COPD) and emphysema, the structural changes that reduce the amount of elastic recoil, lead to loss of pulmonary function. We recently demonstrated that elastin is a target of peptidyl arginine deiminase (PAD) enzyme-induced citrullination, thereby leading to enhanced susceptibility of this ECM protein to proteolysis. This study aimed to investigate the impact of PAD activity in vivo and furthermore assessed whether pharmacological inhibition of PAD activity protects against pulmonary emphysema. Using a Serpina1a-e knockout mouse model, previously shown to develop inflammation-mediated emphysema, we validated the involvement of PADs in airway disease. In line with emphysema development, intratracheal administration of lipopolysaccharide in combination with PADs provoked significant airspace enlargement ( P < 0.001) and diminished lung function, including loss of lung tissue elastance ( P = 0.0217) and increases in lung volumes ( P = 0.0463). Intraperitoneal treatment of mice with the PAD inhibitor, BB-Cl-amidine, prevented PAD/LPS-mediated lung function decline and emphysema and reduced levels of citrullinated airway elastin ( P = 0.0199). These results provide evidence for the impact of PADs on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD. NEW & NOTEWORTHY This study provides evidence for the impact of peptidyl arginine deiminase (PAD) enzymes on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD. |