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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)275-287
Number of pages13
JournalFree Radical Biology and Medicine
Volume143
DOIs
StatePublished - Nov 1 2019
Externally publishedYes

Fingerprint

Platelet Activating Factor
p38 Mitogen-Activated Protein Kinases
Oxidative stress
Disseminated Intravascular Coagulation
WEB 2086
Coagulation
Acetylcysteine
Oxidative Stress
Platelets
Fibrinogen
Antioxidants
MAP Kinase Kinase 4
Gallic Acid
Tocopherols
Macrophages
Platelet Aggregation Inhibitors
Prothrombin Time
Peritoneal Macrophages
Prothrombin
Sudden Death

Keywords

  • Disseminated intravascular coagulation
  • Oxidative stress
  • p38 MAP-kinase
  • Platelet activating factor
  • Platelet aggregation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Abhilasha, K. V., Sumanth, M. S., Chaithra, V. H., Jacob, S. P., Thyagarajan, A., Sahu, R. P., ... Marathe, G. K. (2019). p38 MAP-kinase inhibitor protects against platelet-activating factor-induced death in mice. Free Radical Biology and Medicine, 143, 275-287. https://doi.org/10.1016/j.freeradbiomed.2019.08.019

p38 MAP-kinase inhibitor protects against platelet-activating factor-induced death in mice. / Abhilasha, Kandahalli Venkataranganayaka; Sumanth, Mosale Seetharam; Chaithra, Vyala Hanumanthareddy; Jacob, Shancy Petsel; Thyagarajan, Anita; Sahu, Ravi Prakash; Rajaiah, Rajesh; Prabhu, K. Sandeep; Kemparaju, Kempaiah; Travers, Jeffrey Bryant; Chen, Chu Huang; Marathe, Gopal Kedihithlu.

In: Free Radical Biology and Medicine, Vol. 143, 01.11.2019, p. 275-287.

Research output: Contribution to journalArticle

Abhilasha, KV, Sumanth, MS, Chaithra, VH, Jacob, SP, Thyagarajan, A, Sahu, RP, Rajaiah, R, Prabhu, KS, Kemparaju, K, Travers, JB, Chen, CH & Marathe, GK 2019, 'p38 MAP-kinase inhibitor protects against platelet-activating factor-induced death in mice', Free Radical Biology and Medicine, vol. 143, pp. 275-287. https://doi.org/10.1016/j.freeradbiomed.2019.08.019
Abhilasha, Kandahalli Venkataranganayaka ; Sumanth, Mosale Seetharam ; Chaithra, Vyala Hanumanthareddy ; Jacob, Shancy Petsel ; Thyagarajan, Anita ; Sahu, Ravi Prakash ; Rajaiah, Rajesh ; Prabhu, K. Sandeep ; Kemparaju, Kempaiah ; Travers, Jeffrey Bryant ; Chen, Chu Huang ; Marathe, Gopal Kedihithlu. / p38 MAP-kinase inhibitor protects against platelet-activating factor-induced death in mice. In: Free Radical Biology and Medicine. 2019 ; Vol. 143. pp. 275-287.
@article{a3e2e2093d1e4c7f97fefbd0677ed40c,
title = "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.",
keywords = "Disseminated intravascular coagulation, Oxidative stress, p38 MAP-kinase, Platelet activating factor, Platelet aggregation",
author = "Abhilasha, {Kandahalli Venkataranganayaka} and Sumanth, {Mosale Seetharam} and Chaithra, {Vyala Hanumanthareddy} and Jacob, {Shancy Petsel} and Anita Thyagarajan and Sahu, {Ravi Prakash} and Rajesh Rajaiah and Prabhu, {K. Sandeep} and Kempaiah Kemparaju and Travers, {Jeffrey Bryant} and Chen, {Chu Huang} and Marathe, {Gopal Kedihithlu}",
year = "2019",
month = "11",
day = "1",
doi = "10.1016/j.freeradbiomed.2019.08.019",
language = "English (US)",
volume = "143",
pages = "275--287",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - p38 MAP-kinase inhibitor protects against platelet-activating factor-induced death in mice

AU - Abhilasha, Kandahalli Venkataranganayaka

AU - Sumanth, Mosale Seetharam

AU - Chaithra, Vyala Hanumanthareddy

AU - Jacob, Shancy Petsel

AU - Thyagarajan, Anita

AU - Sahu, Ravi Prakash

AU - Rajaiah, Rajesh

AU - Prabhu, K. Sandeep

AU - Kemparaju, Kempaiah

AU - Travers, Jeffrey Bryant

AU - Chen, Chu Huang

AU - Marathe, Gopal Kedihithlu

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

KW - Disseminated intravascular coagulation

KW - Oxidative stress

KW - p38 MAP-kinase

KW - Platelet activating factor

KW - Platelet aggregation

UR - http://www.scopus.com/inward/record.url?scp=85070953082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070953082&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2019.08.019

DO - 10.1016/j.freeradbiomed.2019.08.019

M3 - Article

C2 - 31442556

AN - SCOPUS:85070953082

VL - 143

SP - 275

EP - 287

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -