The role of poly(ADP-ribose) polymerase-1 inhibitor in carrageenan-induced lung inflammation in mice.

Abstract

Increasing indication is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulation of inflammatory/immune responses. The aim of the present study was to determine the potential anti-inflammatory effects of PARP-1 inhibitor 5-aminoisoquinolinone (5-AIQ) to explore the role of PARP-1 inhibitor in a mouse model of carrageenan-induced lung inflammation. A single dose of 5-AIQ (1.5mg/kg) was administered intraperitoneally (i.p.) 1h before λ-carrageenan (Cg) administration. We assessed the effects of 5-AIQ treatment on CD25(+), GITR(+), CD25(+)GITR(+), IL-17(+) and Foxp3(+) cells which were investigated using flowcytometry in pleural exudates and heparinized blood. We also evaluated mRNA expressions of IL-6, TNF-α, IL-1β, IL-10, CD11a, l-selectin (CD62L), ICAM-1, MCP-1, iNOS and COX-2 in the lung tissue. We further examined the effects of 5-AIQ on the key mediators of inflammation, namely COX-2, STAT-3, NF-kB p65, PARP-1, IkB-α and IL-4 protein expression in the lung tissue using western blotting. The results illustrated that the numbers of T cell subsets, IL-17(+) cytokine levels were markedly increased and Foxp3(+) production decreased in the Cg group. Furthermore, Cg-induced up-regulation of adhesion molecules, pro-inflammatory mediators and chemokine expressions. Western blot analysis revealed an increased protein expressions of COX-2, STAT-3 NF-kB p65 and PARP-1 and decreased IkB-α and IL-4 in the Cg group. PARP-1 inhibitor via 5-AIQ treatment reverses the action significantly of all the previously mentioned effects. Moreover, histological examinations revealed anti-inflammatory effects of 5-AIQ, whereas Cg-group aggravated Cg-induced inflammation. Present findings demonstrate the potent anti-inflammatory action of the PARP-1 inhibitor in acute lung injury induced by carrageenan.

• Authors: Sheikh Fayaz Ahmad, Khairy M A Zoheir, Mushtaq Ahmad Ansari, Hesham M Korashy, Saleh A Bakheet, Abdelkader E Ashour, Othman A Al-Shabanah, Mohammed M Al-harbi, Sabry M Attia
• Journal: Molecular immunology (Mol Immunol) Vol. 63 Issue 2 Pg. 394-405 (Feb 2015) ISSN: 1872-9142 [Electronic] England
• PMID: 25304310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• 5-aminoisoquinolinone
• Cell Adhesion Molecules
• Cytokines
• Enzyme Inhibitors
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Glucocorticoid-Induced TNFR-Related Protein
• Inflammation Mediators
• Interleukin-17
• Interleukin-2 Receptor alpha Subunit
• Isoquinolines
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA, Messenger
• Tnfrsf18 protein, mouse
• Carrageenan
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Carrageenan
• Cell Adhesion Molecules (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Cytokines (genetics, metabolism)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Forkhead Transcription Factors (metabolism)
• Gene Expression Regulation (drug effects)
• Glucocorticoid-Induced TNFR-Related Protein (metabolism)
• Inflammation Mediators (metabolism)
• Interleukin-17 (biosynthesis)
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Isoquinolines (pharmacology, therapeutic use)
• Lipid Peroxidation (drug effects, genetics)
• Mice, Inbred BALB C
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Pneumonia (drug therapy, enzymology, pathology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA, Messenger (genetics, metabolism)
• T-Lymphocytes, Regulatory (drug effects, metabolism)