Photo Credit: Mohammed Haneefa Nizamudeen

The following is a summary of “Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation,” published in May 2024 issue of Allergy & Immunology by Murphy, et al.

In chronic obstructive pulmonary disease (COPD), inflammation leads to the protease-mediated breakdown of elastin, a critical extracellular matrix protein, resulting in irreversible pulmonary function loss. Efforts to counteract proteolysis in COPD have yielded limited success, partly due to an incomplete understanding of disease mechanisms. Peptidyl arginine deiminase (PAD) enzymes, known to influence proteolytic susceptibility, have not been extensively studied in the context of COPD. 

For a study, researchers sought to investigate the role of PAD enzymes, specifically PAD2 and PAD4, in COPD and their impact on elastin degradation and lung function.

They analyzed neutrophils from individuals with COPD and healthy controls to assess PAD enzyme levels. Bronchoalveolar lavage and lung tissue samples from patients with COPD, also matched smoking and nonsmoking individuals with normal lung function, were examined for PAD concentrations. The study investigated citrullinated elastin in the peripheral airways of patients with COPD and its susceptibility to proteolytic degradation in vitro.

The findings indicated that PAD2 and PAD4 are present in the primary granules of neutrophils, with elevated PAD levels observed in neutrophils from patients with COPD compared to healthy controls. Patients with COPD exhibited significantly higher airway concentrations of PADs. In ex vivo analyses, they identified citrullinated elastin in the peripheral airways of patients with COPD. In vitro experiments demonstrated that citrullinated elastin was more susceptible to proteolytic degradation by serine proteases and matrix metalloproteinases, including neutrophil elastase and matrix metalloproteinase-12.

The study revealed a mechanism by which neutrophil-released PADs contribute to lung function decline in COPD through elastin citrullination and enhanced proteolytic degradation. The findings suggested potential for developing PAD-based therapeutics aimed at preserving lung function in patients with COPD.

Reference: journals.aai.org/jimmunol/article/213/1/75/266890/Neutrophil-Derived-Peptidyl-Arginine-Deiminase