The protective role of Prolyl oligopeptidase (POP) inhibition in acute lung injury induced by intestinal ischemia-reperfusion

Abstract

Intestinal ischemia-reperfusion (II/R) develops when the blood flow to the intestines decreases, followed by the reestablishment of the blood supply to the ischemic tissue, resulting in intestinal mucosal barrier dysfunction, with consequent severe local and systemic inflammation. Acute lung injury (ALI) represents the most serious complication after II/R. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic and inflammatory molecules. The aim of the present study is to assess the effects of POP-inhibition mediated by KYP-2047 treatment in the pathophysiology of ALI following II/R. An in vivo model of II/R was performed and mice were subjected to KYP-2047 treatment (intraperitoneal, 1, 2.5 and 5 mg/ kg). Histological analysis, Masson's trichrome staining, immunohistochemical, immunofluorescence, biochemical and western blots analysis were performed on ileum and lung samples. KYP-2047 treatment ameliorated histological alteration in ileum and lung, reduced collagen amount and lowered inflammatory protein levels. Moreover, TGF-β1, eNOS, VEGF and CD34 positive staining has been modulated; also, a reduction in apoptosis expression was confirmed. This research revealed the strong anti-inflammatory potential of KYP-2047 associated to its modulatory role on angiogenesis and apoptosis, suggesting POP as a novel therapeutic target for ALI after II/R.

Synergistic Pulmonoprotective Effect of Natural Prolyl Oligopeptidase Inhibitors in In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome

“…The POP-associated production of the collagen-derived neutrophil chemoattractant PGP and the self-sustaining neutrophil-driven constant inflammation linked the enzyme to various inflammatory pulmonary conditions, such as COPD and cystic fibrosis [ 18 ]. Previous studies have demonstrated the involvement of POP in inflammation, angiogenesis, oxidative stress and apoptosis, so POP inhibition could be a potential target in order to counteract lung injury [ 15 ]. A number of POP inhibitors, such as the selective inhibitor of POP, KYP-2047 (4-phenyl-butanoyl-l-prolyl-2(S)-cyanopyrrolidine) and valproic acid, have been developed and extensively studied in various in vitro and in vivo models of inflammatory diseases with beneficial effects against these mechanisms that the POP enzyme is involved [ 15 , 83 , 84 ].…”

“…Recent studies have also demonstrated the involvement of the cleaving enzyme prolyl oligopeptidase/endopeptidase (POP/PREP) in ALI [ 15 ]. The pro-inflammatory nature of POP is attributed to its ability to generate the neutrophil chemoattractant matrikine proline-glycine-proline (PGP) from collagen fragments [ 16 ] with the concerted action of metalloproteinases.…”

Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the N-Methyl-d-Aspartate (NMDA) Receptors

“…Hind paw and lumbar spinal cord tissue sections were processed for immunohistochemical analysis, as previously described [ 23 ]. Sections were incubated overnight with: IL-1β (sc-12742, 1:100), scaffolding protein postsynaptic density protein-95 (PSD95) (sc-32291, 1:100) and anti-NMDAε2 (NR2B) (sc-365597, 1:100).…”

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

“…The degree of fibrosis of the renal sections was assessed using Masson’s trichrome stain, following the manufacturer’s instructions (Bio-Optica, Milan, Italy), as previously described [ 73 , 74 ]. This staining allows highlighting connective tissue, collagen, reticular fibers, and muscle fibers.…”