Deficiency of plasma platelet-activating factor (PAF) acetylhydrolase is an autosomal recessive syndrome that has been associated with severe asthma in Japanese children. Acquired deficiency has been described in several human diseases usually associated with severe inflammation. PAF acetylhydrolase catalyzes the degradation of PAF and related phospholipids, which have proinflammatory, allergic, and prothrombotic properties. Thus, a deficiency in the degradation of these lipids should increase the susceptibility to inflammatory and allergic disorders. Miwa et al. reported that PAF acetylhydrolase activity is absent in 4% of the Japanese population, which suggests that it could be a common factor in such disorders, but the molecular basis of the defect is unknown. We show that inherited deficiency of PAF acetylhydrolase is the result of a point mutation in exon 9 and that this mutation completely abolishes enzymatic activity. This mutation is the cause of the lack of enzymatic activity as expression in E. coli of a construct harboring the mutation results in an inactive protein. This mutation as a heterozygous trait is present in 27% in the Japanese population. This finding will allow rapid identification of subjects predisposed to severe asthma and other PAF-mediated disorders. ( J. Clin. Invest. 1996. 97:2784-2791.)

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High LDL and/or low HDL are risk factors for atherosclerosis and are also a common clinical feature in systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Here, we show that changes in lipid profiles that reflect atherosclerotic disease led to activation of skin murine dendritic cells (DCs) locally, promoted dermal inflammation, and induced lymph node hypertrophy. Paradoxically, DC migration to lymph nodes was impaired, suppressing immunologic priming. Impaired migration resulted from inhibitory signals generated by platelet-activating factor (PAF) or oxidized LDL that acts as a PAF mimetic. Normal DC migration and priming was restored by HDL or HDL-associated PAF acetylhydrolase (PAFAH), which mediates inactivation of PAF and oxidized LDL. Thus, atherosclerotic changes can sequester activated DCs in the periphery where they may aggravate local inflammation even as they poorly carry out functions that require their migration to lymph nodes. In this context, HDL and PAFAH maintain a normally functional DC compartment.

Brain inflammation has been implicated in the development of brain edema and secondary brain damage in ischemia and trauma. Adhesion molecules, cytokines and leukocyte chemoattractants released/presented at the site of blood‐brain barrier (BBB) play an important role in mobilizing peripheral inflammatory cells into the brain. Cerebral endothelial cells (CEC) are actively engaged in processes of microvascular stasis and leukocyte infiltration by producing a plethora of pro‐inflammatory mediators. When challenged by external stimuli including cytokines and hypoxia, CEC have been shown to release/express various products of arachidonic acid cascade with both vasoactive and pro‐inflammatory properties, including prostaglandins, leukotrienes, and platelet‐activating factor (PAF). These metabolites induce platelet and neutrophil activation and adhesion, changes in local cerebral blood flow and blood rheology, and increases in BBB permeability. Ischemic CEC have also been shown to express and release bioactive inflammatory cytokines and chemokines, including IL‐Iβ, IL‐8 and MCP‐1. Many of these mediators and ischemia in vitro and in vivo have been shown to up‐regulate the expression of both selectin and Ig‐families of adhesion molecules in CEC and to facilitate leukocyte adhesion and transmigration into the brain. Collectively, these studies demonstrate a pivotal role of CEC in initiating and regulating inflammatory responses in cerebral ischemia. Summary Inflammatory genes/mediators are involved in molecular/biochemical cascades determining stroke outcome. Cerebral endothelial cells, targeted by inflammatory mediators produced in ischemic brain, undergo pro‐inflammatory activation by expressing/secreting various inflammatory mediators, thus becoming a source of inflammation themselves. A unique position of the cerebral endothelial cells at the interface between blood and brain establishes their role as principal regulators of peripheral inflammatory cell recruitment into the brain during stroke. Cerebral endothelial cells also exhibit ability to regulate vasomotor responses of brain microcirculation and the permeability of the BBB, both important components of inflammation. Therefore, approaches to attenuate consequences of stroke must take into consideration cerebral endothelial cells as an easily accessible target to interfere with the ischemic brain inflammation.

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