Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium

Prerna Rastogi; Jane McHowat

doi:10.1016/j.resp.2008.11.006

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Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium

Journal article

Open access

Peer reviewed

Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium

Prerna Rastogi and Jane McHowat

Respiratory physiology & neurobiology, Vol.165(2-3), pp.167-174

02/28/2009

DOI: 10.1016/j.resp.2008.11.006

PMCID: PMC2845306

PMID: 19059366

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Abstract

Inhalation of allergens can result in mast cell degranulation and release of granule contents, including tryptase, in the lung. Injury to human pulmonary microvascular endothelial cells (HMVEC-L) can also result in activation of the coagulation cascade and thrombin generation. We hypothesize that these proteases activate calcium-independent phospholipase A2 (iPLA2), in HMVEC-L, leading to the production of membrane phospholipids-derived inflammatory mediators. Both thrombin and tryptase stimulation of HMVEC-L increased iPLA2 activity that was inhibited by pretreatment with the iPLA2 selective inhibitor bromoenol lactone (BEL). Arachidonic acid and prostaglandin I2 (PGI2) release were also increased in tryptase and thrombin stimulated cells and inhibited by BEL pretreatment. Pretreating the endothelial cells with AACOCF3 a cytosolic PLA2 inhibitor did not inhibit tryptase or thrombin induced arachidonic acid and PGI2 release. In addition thrombin and tryptase also increased HMVEC-L platelet activating factor (PAF) production that significantly contributes to the recruitment and initial adherence of polymorphonuclear neutrophils (PMN) to the endothelium. Tryptase or thrombin stimulated increase in PMN adherence to the endothelium was inhibited by pretreatment of HMVEC-L with BEL or pretreatment of PMN with CV3988, a PAF receptor specific antagonist. Collectively, these data support our hypothesis that iPLA2 activity is responsible for membrane phospholipid hydrolysis in response to tryptase or thrombin stimulation in HMVEC-L. Therefore selective inhibition of iPLA2 may be a pharmacological target to inhibit the early inflammation in pulmonary vasculature that occurs as a consequence of mast cell degranulation or acute lung injury.

Neutrophils - cytology

Arachidonic Acid - metabolism

Epoprostenol - metabolism

Humans

Cells, Cultured

Hypersensitivity - immunology

Phosphodiesterase Inhibitors - pharmacology

Cell Adhesion - drug effects

Enzyme Activation - drug effects

Group VI Phospholipases A2 - metabolism

Pyrones - pharmacology

Naphthalenes - pharmacology

Cell Adhesion - immunology

Endothelial Cells - immunology

Platelet Activating Factor - metabolism

Thrombin - pharmacology

Group VI Phospholipases A2 - antagonists & inhibitors

Hypersensitivity - metabolism

Endothelial Cells - cytology

Inflammation Mediators - metabolism

Tryptases - pharmacology

Lung - blood supply

Endothelial Cells - enzymology

Enzyme Activation - physiology

Details

Title: Subtitle: Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium
Creators: Prerna Rastogi - Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
Jane McHowat
Resource Type: Journal article
Publication Details: Respiratory physiology & neurobiology, Vol.165(2-3), pp.167-174
DOI: 10.1016/j.resp.2008.11.006
PMID: 19059366
PMCID: PMC2845306
NLM abbreviation: Respir Physiol Neurobiol
ISSN: 1569-9048
eISSN: 1878-1519
Publisher: Netherlands
Grant note: R01 HL068588 / NHLBI NIH HHS R01 HL068588-04 / NHLBI NIH HHS HL-68588 / NHLBI NIH HHS
Language: English
Date published: 02/28/2009
Academic Unit: Pathology
Record Identifier: 9984047730802771

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