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.