p38 MAP-kinase inhibitor protects against platelet-activating factor-induced death in mice.

Abstract

Platelet-activating factor (PAF) is a potent inflammatory agonist. In Swiss albino mice, intraperitoneal injection of PAF causes sudden death with oxidative stress and disseminated intravascular coagulation (DIC), characterized by prolonged prothrombin time, thrombocytopenia, reduced fibrinogen content, and increased levels of fibrinogen degradation products. However, the underlying mechanism(s) is unknown. The PAF-R antagonist WEB-2086 protected mice against PAF-induced death by reducing DIC and oxidative stress. Accordingly, general antioxidants such as ascorbic acid, α-tocopherol, gallic acid, and N-acetylcysteine partially protected mice from PAF-induced death. N-acetylcysteine, a clinically used antioxidant, prevented death in 67% of mice, ameliorated DIC characteristics and histological alterations in the liver, and reduced oxidative stress. WEB-2086 suppressed H2O2-mediated oxidative stress in isolated mouse peritoneal macrophages, suggesting that PAF signaling may be a downstream effector of reactive oxygen species generation. PAF stimulated all three (ERK, JNK, and p38) of the MAP-kinases, which were also inhibited by N-acetylcysteine. Furthermore, a JNK inhibitor (SP600125) and ERK inhibitor (SCH772984) partially protected mice against PAF-induced death, whereas a p38 MAP-kinase inhibitor (SB203580) provided complete protection against DIC and death. In human platelets, which have the canonical PAF-R and functional MAP-kinases, JNK and p38 inhibitors abolished PAF-induced platelet aggregation, but the ERK inhibitor was ineffective. Our studies identify p38 MAP-kinase as a critical, but unrecognized component in PAF-induced mortality in mice. These findings suggest an alternative therapeutic strategy to address PAF-mediated pathogenicity, which plays a role in a broad range of inflammatory diseases.

• Authors: Kandahalli Venkataranganayaka Abhilasha, Mosale Seetharam Sumanth, Vyala Hanumanthareddy Chaithra, Shancy Petsel Jacob, Anita Thyagarajan, Ravi Prakash Sahu, Rajesh Rajaiah, K Sandeep Prabhu, Kempaiah Kemparaju, Jeffrey Bryant Travers, Chu-Huang Chen, Gopal Kedihithlu Marathe
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 143 Pg. 275-287 (11 01 2019) ISSN: 1873-4596 [Electronic] United States
• PMID: 31442556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Free Radical Scavengers
• Platelet Activating Factor
• Protective Agents
• Reactive Oxygen Species
• p38 Mitogen-Activated Protein Kinases
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Death, Sudden (etiology, pathology, prevention & control)
• Enzyme Inhibitors (pharmacology)
• Female
• Free Radical Scavengers (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Platelet Activating Factor (toxicity)
• Protective Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)