title: Lung endothelial cell platelet-activating factor production and inflammatory cell adherence are increased in response to cigarette smoke component exposure.
abstract: An early event in the pathogenesis of emphysema is the development of inflammation associated with accumulation of polymorphonuclear leukocytes (PMN) in small airways, and inflammatory cell recruitment from the circulation involves migration across endothelial and epithelial cell barriers. Platelet-activating factor (PAF) promotes transendothelial migration in several vascular beds, and we postulated that increased PAF production in the airways of smokers might enhance inflammatory cell recruitment and exacerbate inflammation. To examine this possibility, we incubated human lung microvascular endothelial cells (HMVEC-L) with cigarette smoke extract (CSE) and found that CSE inhibits PAF-acetylhydrolase (PAF-AH) activity. This enhances HMVEC-L PAF production and PMN adherence, and adherence is blocked by PAF receptor antagonists (CV3988 or ginkgolide B). CSE also inhibited PAF-AH activity of lung endothelial cells isolated from wild-type (WT) and iPLA(2)β knockout mice, and with WT cells, CSE enhanced PAF production and RAW 264.7 cell adherence. In contrast, CSE did not affect PAF production or RAW 264.7 cell adherence to iPLA(2)β-null cells, suggesting that iPLA(2)β plays an important role in PAF production by lung endothelial cells. These findings suggest that inhibition of PAF-AH by components of cigarette smoke may initiate or exacerbate inflammatory lung disease by enhancing PAF production and promoting accumulation of inflammatory cells in small airways. In addition, iPLA(2)β is identified as a potential target for therapeutic interventions to reduce airway inflammation and the progression of chronic lung disease.
authors: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors: Janhavi
authors: J
authors: Sharma
authors: Dawn M
authors: DM
authors: Young
authors: John O
authors: JO
authors: Marentette
authors: Prerna
authors: P
authors: Rastogi
authors: John
authors: J
authors: Turk
authors: Jane
authors: J
authors: McHowat
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D054522:Group VI Phospholipases A2 / Q000172:deficiency / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014028:Tobacco Smoke Pollution; C039351:platelet activating factor receptor; C037913:CV 3988; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase