Neutralizing Ceramide: A Major Breakthrough or Yet Another Marginal Target for the Treatment of Acute Lung Injury? A review of Göggel R, Winoto-Morbach S, Vielbaher G, Imai Y, Lindner K, Brade L, Brade H, Ehlers S, Slutsky AS, Schütze S, Gulbins E, Uhlig S 2004 PAF-induced pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med 10:155–160. A cute lung injury (ALI) is a com- plication of various disorders, in- cluding toxic inhalation, viral pneumo- nia, and sepsis, that literally drowns patients suffering from these condi- tions. The physiopathological mecha- nisms that cause alveolar flooding, which effectively impair gas exchange, were unraveled many years ago (1). However, the intricate cellular and mo- lecular mechanisms underlying alveo- lar flooding remain elusive, and the search for an understanding of how and when lung cells begin losing their normal function, becoming weak and leaky, remains a vital quest. Many mediators have been impli- cated in ALI and the acute respiratory distress syndrome (ARDS), including tumor necrosis factor-  (TNF- ), platelet-activating factor (PAF) and prostaglandins (2). Because there are probably several interacting mecha- nisms involved, blocking a single me- diator has not proven effective against ALI in clinical trials. In many experi- mental models of ALI, edema forma- tion is mediated by PAF (3). Moreover, application of recombinant PAF acetyl- hydrolase markedly decreases vascular leakage in animal models (4), and has shown promising results in phase 2 clin- ical trials for severe sepsis (5). The molecular mechanisms by which PAF triggers edema formation are poorly understood. Using the iso- lated, perfused lung, edema formation can be easily monitored by measuring lung weight. In addition, the two con- founding factors observed in the in vivo model of pulmonary hypertension are excluded. First, by perfusing the lungs with constant hydrostatic pres- sure, the confounding effects of pulmo- nary hypertension are excluded, and second by using of a blood-free per- fusate, blood-borne leukocytes are eliminated. Using this model, PAF was recently shown to trigger edema by increasing microvascular permeability through two independent mechanisms. One pathway involves activation of EP-3 receptors by prostaglandin E 2 , which can be blocked by cyclo- oxygenase inhibitors such as acetyl salicylic acid (ASA) (6). The nature of the other pathway is elusive. Based on the observation that PAF stimulates ceramide formation in mouse macro- phages (7), the authors hypothesized that ceramide is involved in PAF- induced edema formation. Ceramide (N-acyl-sphingosine) is a lipid that lies within the cell membrane bilayer, forming the backbone for gly- cosphingolipids. More than a simple hydrophobic moiety anchoring glyco- lipid molecules in the membrane bi- layer, ceramide is also known to func- tion as a signaling molecule (Fig. 1). Ceramide is produced from membrane sphingomyelin by several sphingomy- elinases, one of which is the secretory acid sphingomyelinase (SA-SMase), which is activated by several inflam- matory mediators including PAF. There are at least two alternative path- ways that can be followed by ceramide generated at the outer leaflet of the membrane. Either ceramide flips in- wards and undergoes hydrolysis by ce- ramidase to generate sphingosine, which is, in turn, reversibly phosphor- ylated by sphingosine kinase to give sphingosine-1-phosphate (S1P). Alter- natively, sphingomyelin synthase cata- lyzes the transfer of the phosphoryl- choline moiety from one molecule of phosphatidylcholine to one molecule of ceramide to form one molecule of sphingomyelin and one molecule of diacylglycerol (DAG) (8). DAG acti- vates protein kinase C (PKC). Both PKC and sphingosine-1-phosphate can activate the transcription factor, nu- clear factor-B (NF-B). Note that the enzyme sphingosine kinase can be ac- tivated by TNF, thus providing an- other mean to stimulate S1P by inflam- matory mediators (9,10). Mediators derived from ceramide can also cause apoptosis (11), either by means of S1P formation or through activation of DAG-PKC pathway, hence further worsening the tissue damage that was already triggered by inflammatory processes. In the present study, SA-SMase- deficient or wild-type mice were treated with PAF. Following PAF ad- ministration, normal mice developed pulmonary edema within 10 min; whereas, in SA-SMase-deficient mice, or wild-type mice pretreated with ASA, pulmonary edema was reduced by ~50%. Treatment of SA-SMase- deficient mice with ASA completely eliminated PAF-induced edema, indi- cating that PAF-induced edema is me- diated by the combined action of SA- JEAN-CHRISTOPHE MERCIER, A. TUAN DINH-XUAN RESEARCH NEWS 319 0031-3998/05/5703-0319 PEDIATRIC RESEARCH Vol. 57, No. 3, 2005 Copyright © 2005 International Pediatric Research Foundation, Inc. Printed in U.S.A.