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.

Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis

“…19,43,44 In this current study, we were able to confirm that PAFR is important for the inflammatory process, not only contributing to chemotaxis, but also activating innate and adaptive immune responses. PAF and its receptor have been widely linked to inflammation, 27,[45][46][47][48] and is interesting to highlight that not only immune cells, but also a great variety of cell types, from different organs, show an increase in inflammatory signaling as a response to PAF, for example, activating NF-kB, promoting superoxide …”

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

“…Sharma et al (109) found that CSE inhibits platelet-activating factor (PAF) acetylhydrolase activity, which enhances PAF production and PMN adherence. Similarly, Meyer et al (83) showed that the expression of secretory leukoprotease inhibitor (SLPI) is regulated by Stat1, and both are increased in nasal epithelial cells and BALF of smokers, indicating that altered SLPI regulation and activity induced by CS could play a role in the development of respiratory inflammation and infection.…”

Mice with Genetic Deletion of Group VIA Phospholipase A 2 β Exhibit Impaired Macrophage Function and Increased Parasite Load in Trypanosoma cruzi-Induced Myocarditis

“…Our previous in vitro studies indicated that iPLA 2 ␤ is critical for recruiting inflammatory cells to the endothe-lium via the production of PAF (4,6). Thus, we measured PAF production and the expression of adhesion molecules in cardiac endothelial cells isolated from WT and iPLA 2 ␤-KO mice (Fig.…”

“…Our group has previously demonstrated increased expression of platelet-activating factor (PAF), in addition to the upregulation of adhesion molecules, in human coronary artery endothelial cells (HCAECs) acutely infected with T. cruzi (4). The role of PAF in the recruitment, transmigration, and activation of inflammatory cells is well established (5)(6)(7)(8).…”