A new zinc chelator, IPZ-010 ameliorates postoperative ileus.
Adenosine Triphosphate
/ pharmacology
Animals
Anti-Inflammatory Agents
/ pharmacology
Antigens, CD
/ metabolism
Antigens, Differentiation, Myelomonocytic
/ metabolism
Chelating Agents
/ chemistry
Disease Models, Animal
Ethylenediamines
/ pharmacology
Gastrointestinal Transit
/ drug effects
Ileus
/ drug therapy
Inflammation Mediators
/ metabolism
Ketotifen
/ pharmacology
Lipopolysaccharides
/ pharmacology
Macrophages
/ metabolism
Mast Cells
/ drug effects
Mice, Inbred BALB C
Mice, Inbred C57BL
Neutrophils
/ metabolism
Postoperative Complications
/ drug therapy
RNA, Messenger
/ genetics
Zinc
/ metabolism
Inflammation
Macrophages
Mast cells
Postoperative ileus
Zinc
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
01
10
2019
revised:
29
11
2019
accepted:
04
12
2019
pubmed:
22
12
2019
medline:
4
11
2020
entrez:
22
12
2019
Statut:
ppublish
Résumé
Zinc was discovered to be a novel second messenger in immunoreactive cells. We synthesized a novel free zinc chelator, IPZ-010. Here, we investigated the effects of IPZ-010 in a mouse postoperative ileus model and determined the effects of zinc signal inhibition as a new therapeutic strategy against postoperative ileus. Zinc waves were measured in bone marrow-derived mast cells (BMMCs) loaded with a zinc indicator, Newport green. Degranulation and cytokine expression were measured in BMMCs and bone marrow-derived macrophages (BMDMs). Postoperative ileus model mice were established with intestinal manipulation. Mice were treated with IPZ-010 (30 mg/kg, s.c. or p.o.) 1 h before and 2 h and 4 h after intestinal manipulation. Gastrointestinal transit, inflammatory cell infiltration, and expression of inflammatory mediators were measured. Free zinc waves occurred following antigen stimulation in BMMCs and were blocked by IPZ-010. IPZ-010 inhibited interleukin-6 secretion and degranulation in BMMCs. IPZ-010 inhibited tumor necrosis factor-α mRNA expression in BMMCs stimulated with lipopolysaccharide or adenosine triphosphate, whereas IPZ-010 had no effects on tumor necrosis factor-α mRNA expression in BMDMs stimulated with lipopolysaccharide or adenosine triphosphate. In postoperative ileus model mice, IPZ-010 inhibited leukocyte infiltration and cytokine expression, which ameliorated gastrointestinal transit. Furthermore, ketotifen (1 mg/kg) induced similar effects as IPZ-010. These effects were not amplified by co-administration of IPZ-010 and ketotifen. IPZ-010 inhibited zinc waves, resulting in inhibition of inflammatory responses in activated BMMCs in vitro. Targeting zinc waves in inflammatory cells may be a novel therapeutic strategy for treating postoperative ileus.
Identifiants
pubmed: 31862476
pii: S0753-3322(19)35395-8
doi: 10.1016/j.biopha.2019.109773
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Antigens, CD
0
Antigens, Differentiation, Myelomonocytic
0
CD68 antigen, human
0
Chelating Agents
0
Ethylenediamines
0
Inflammation Mediators
0
Lipopolysaccharides
0
RNA, Messenger
0
Adenosine Triphosphate
8L70Q75FXE
Zinc
J41CSQ7QDS
N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
R9PTU1U29I
Ketotifen
X49220T18G
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
109773Informations de copyright
Copyright © 2019. Published by Elsevier Masson SAS.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.