The proline isomerase Pin1 inhibitors PiB and juglone protect rats against lipopolysaccharide-induced respiratory inflammation.

Abstract

The peptidyl-prolyl cis/trans-isomerase, NIMA-interacting 1 (Pin1), is involved in several cellular functions by changing the conformation and activity of phosphorylated proteins. Its key role in cellular signalling makes Pin1 an appealing target for the development of pharmacological agents to treat diseases such as inflammation. Pulmonary inflammation is a major disease resulting from the activation of immune cells by microbes or pollutants. In this study, we examined the effects of two Pin1 inhibitors, PiB and juglone, on lipopolysaccharide (LPS)-induced pulmonary inflammation in rats. Our results demonstrate that the intraperitoneal (i.p.) administration of 3 mg/kg of PiB and juglone mitigates LPS-induced pulmonary inflammation by reducing haemorrhage, vascular injury, pulmonary oedema and immune cell accumulation in the airway region. Furthermore, these Pin1 inhibitors were found to protect rats against the overproduction of inflammatory markers by inhibiting myeloperoxidase (MPO) and lactate dehydrogenase (LDH) activities, as well as reducing plasma C-reactive protein (C-RP). Additionally, PiB and juglone protected the rats from nitric oxide synthase (NOS) hyperactivity, preventing oxidative stress by decreasing pro-oxidant markers and restoring the antioxidant enzymes such as catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). The use of juglone and PiB could therefore be an effective means of alleviating acute respiratory inflammation by modulating inflammatory and oxidant pathways and preserving lung microstructure.