Antioxidant Glutathione Analogues UPF1 and UPF17 Modulate the Expression of Enzymes Involved in the Pathophysiology of Chronic Obstructive Pulmonary Disease.

Abstract

Increased oxidative stress (OS) and systemic inflammation are key players in the pathophysiology of chronic obstructive pulmonary disease (COPD). We aimed to clarify the effects of synthetic glutathione (GSH) analogue peptides UPF1 and UPF17 on the mRNA levels of enzymes involved in systemic inflammation and GSH metabolism in peripheral blood mononuclear cells (PBMCs) from patients with acute exacerbation of COPD (AE-COPD) and stable COPD along with non-obstructive smokers and non-smokers. UPF1 and UPF17 increased the expression of enzymes involved in the formation of the antioxidant capacity: superoxide dismutase 1 (SOD1) and the catalytic subunit of glutamyl-cysteine ligase (GCLC) in patients with AE-COPD and stable COPD, but also in non-obstructive smokers and non-smokers. Similarly, both UPF1 and UPF17 increased the expression of inflammatory enzymes poly(ADP-ribose) polymerase-1 (PARP-1), dipeptidyl peptidase 4 (DPP4), and cyclooxygenase-2 (COX-2). Both UPF analogues acted in a gender-dependent manner by increasing the expression of certain anti-inflammatory (histone deacetylase 2 (HDAC2)) and GSH metabolism pathway (SOD1 and GSH reductase (GSR))-related enzymes in females and decreasing them in males. UPF1 and UPF17 are able to increase the expression of the enzymes involved in GSH metabolism and could serve as a lead for designing potential COPD therapies against excessive OS.