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Abstract
A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by neutrophils and present in COPD serum and sputum. Valproic acid (VPA) is an inhibitor of PE and could possibly have an effect on the severity of chronic inflammation. Here the interaction site of VPA to PE and the resulting effect on the secondary structure of PE is investigated. Also, the potential inhibition of PGP-generation by VPA was examined in vitro and in vivo to improve our understanding of the biological role of VPA. UV- visible, fluorescence spectroscopy, CD and NMR were used to determine kinetic information and structural interactions between VPA and PE. In vitro, PGP generation was significantly inhibited by VPA. In vivo, VPA significantly reduced cigarette-smoke induced neutrophil influx. Investigating the molecular interaction between VPA and PE showed that VPA modified the secondary structure of PE, making substrate binding at the catalytic side of PE impossible. Revealing the molecular interaction VPA to PE may lead to a better understanding of the involvement of PE and PGP in inflammatory conditions. In addition, the model of VPA interaction with PE suggests that PE inhibitors have a great potential to serve as therapeutics in inflammatory disorders.
Highlights
chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by airflow limitation that is not fully reversible
A drug used in bipolar disease as well, showed no effect on the activity of prolyl endopeptidase (PE) at the same dose range as Valproic acid (VPA) (0–10 mM VPA on top of PE:ZPP (10 mM)), similar to the findings of Cheng et al [12]
Adding up to 24 mM VPA on top of the PE:ZPP mixture did not show any change in signal. These results suggest that VPA changes the secondary structure of recombinant human PE (rhPE) by binding at or near the binding pocket of rhPE
Summary
COPD is defined as a disease state characterized by airflow limitation that is not fully reversible. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. PGP acts as a neutrophil chemoattractant in vitro and induces neutrophilic inflammation when instilled into the airways of mice in-vivo. Chronic N-a-PGP administration into murine airways for 12 weeks at biweekly intervals leads to the development of neutrophilic airway inflammation, alveolar enlargement, and right ventricular hypertrophy, all of which are features of COPD. Gaggar et al have gone on to demonstrate a prominent role for this peptide in additional inflammatory neutrophilic lung conditions, such as cystic fibrosis (CF) and chronic allograft rejection after lung transplantation [3,5]
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