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Role of platelet activating factor in pathogenesis of acute respiratory distress syndrome

XU, Wei; XIA, Shi-hai; WANG, Huo; CHEN, Hong; WANG, Yu-liang

Medical progress

Laboratory of Digestive Medicine, Affiliated Hospital of Medical College of Armed Police Forces of People's Republic of China, Tianjin 300162, China (Xu W, Xia SH and Wang YL)

Department of Respiratory Medicine, Affiliated Hospital of Medical College of Armed Police Forces of People's Republic of China, Tianjin 300162, China (Wang H and Chen H)

Correspondence to: Dr. XIA Shi-hai, Laboratory of Digestive Medicine, Affiliated Hospital of Medical College of Armed Police Forces of People's Republic of China, Tianjin 300162, China (Tel: 86-22-60578765. Fax: 86-22-24370605.

This work was supported by a grant from the National Natural Science Foundation of China (No. 30300465).

(Received April 30, 2007)

Edited by CHEN Li-min

The acute respiratory distress syndrome (ARDS) is defined by noncardiogenic pulmonary edema and acute respiratory failure in the seriously ill patients. It represents the serious pulmonary response to a broad range of severe injuries occurring either directly to the lung or as the consequence of injury or inflammation at other sites in the body. With the great advance in the treatment of serious diseases such as severe trauma, shock and sepsis, many patients do not die of original diseases but develop ARDS, which makes the incidence of ARDS increase. Results from a recent thorough epidemiological study conducted in Seattle suggested ARDS incidence figure of 59 cases per 100 000 inhabitants/year.1

The pathogenesis of ARDS is not well understood. In its development, harmful factors directly injure alveolar membrane. But what is more important is that various inflammatory cells such as macrophages, polymer-phonuclear neutrophils (PMN) and platelets, and inflammatory mediators indirectly mediate pulmonary inflammatory reactions, which ultimately leads to alveolar membrane injury, increase in permeability and microthromb formation. They also injure alveolar epithelium, diminish and eliminate alveolar surfactant, and exacerbate lung edema and atelectasis, resulting in dysfunction of pulmonary gas-blood exchange and refractory hypoxemia.

Among the inflammatory mediators which are involved in the pathogenesis of ARDS, platelet activating factor (PAF) has received more and more attention in recent years. PAF is one of the most potent and versatile pro-inflammatory mediators. It has been found to increase in lungs2,3 and plasma4,5 of experimental animals and bronchoalveolar lavage fluid (BALF) of patients.6,7 Experimental studies indicate that PAF significantly activates neutrophils, enhances the release of other cytokines and chemokines, increases vascular permeability and pressure in the pathogensis of ARDS. The use of several PAF antagonists attenuated the severity of lung injury. Furthermore, overexpression of platelet activating factor receptor (PAF-R) gene in transgenic mice enhanced lung injury, pulmonary edema, and deterioration of gas exchange caused by HCl aspiration in an experimental study, while mice carrying a targeted disruption of the PAF-R gene experienced significantly less acid-induced injury, edema, and respiratory failure.8 All these studies suggest the important role of PAF in ARDS.

Here we review the role of PAF in several important pathophysiological mechanisms of ARDS, and highlight the beneficial effect of PAF antagonists in animal models.

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PAF is a family of phosphorylcholine esters with diverse potent physiological effects. It is closely associated with the cell membrane. Numerous cell types and tissues have been shown to synthesize and release PAF upon stimulation and at the same time to exhibit biological responses to it.9

There are two metabolic pathways involved in the biosynthesis of PAF, the remodeling and the de novo. The remodeling pathway synthesizes PAF by modifying existing membrane phospholipids, and is the pathway observed in most tissues. The de novo pathway is active in the absence of specific stimulation. It remains the baseline level of PAF in normal condition and is not responsive to inflammatory agents.10 The main degradation pathway of PAF includes that PAF-acetylhydrolase (PAF-AH) cleaving the short acyl chain at sn-2 position to form biologically inactive lyso-PAF,11 which in the remodeling pathway forms PAF, thus completing a metabolic turnover.

In vivo PAF causes increased pulmonary vascular permeability, vasoconstriction, airway hyperreactivity,12-14 hypotension, decreased cardiac output, stimulation of uterine contraction, gastrointestinal disorders, acute bronchoconstriction, and leukocyte adhesion to endothelial cells. In vitro PAF can activate platelets, PMNs, monocytes, and macrophages and stimulate glycogenolysis in perfused liver. Recent studies found PAF caused intensive vessel vasoconstrictor in isolated blood-perfused rat liver,15 enhanced non-rapid eye movement sleep but not rapid eye movement sleep in rabbits16 and induced angiogenesis in rat striatum.17

PAF implements its biological effects by binding to its specific receptor PAF-R. PAF-R is distributed widely in various cells and tissues, including platelets, neutrophils, macrophages, mononuclear leucocytes, lung and liver membrane eosinophils and Kupffer cells. By binding to PAF-R, PAF activates multiple intercellular signaling pathways in various cell types.

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The pathogenesis of ARDS is driven by an aggressive inflammatory reaction, which manifests as systemic inflammatory response syndrome (SIRS). Generally speaking, SIRS is an entirely normal response to injury. But when its resultant systemic leukocyte activation is excessive, leukocytes are activated within the general circulation and many leukocytes then move into and lodge within the pulmonary microcirculation, pulmonary interstitial and alveolar spaces. Leukocytic infiltration,2,18 accumulation of leukocytes in the pulmonary circulation and the microscopic evidence of leukocyte sequestration in pulmonary capillary beds5,19,20 has been proved in animal models of ARDS. Activated leukocytes produce and release free radicals, inflammatory mediators and proteases, which damage capillary endothelium and lung epithelium.

PAF is a potent leukocyte activator, it activates many leukocytes such as monocytes, macrophages, eosinophils, neutrophils and platelets. PAF induces expression of adhesive molecules; promotes chemotaxis, aggregation, granule secretion and oxygen radical generation of leukocytes; enhances adhesion of leukocytes to endothelium.

Neutrophil is the dominant leukocyte found both in BALF and histological specimens from patients with ARDS21 and experimental animals. There was increased neutrophil activation and adhesion molecule expression in BALF of ARDS patients.22 Lung injury is prevented or attenuated if neutrophils are suppressed by its antibody or neutrophil influx was ablated.23,24

PAF primed PMNs isolated from human in a dose- and time-dependent manner in vitro.25 Extravascular PAF infusion induced PMN and platelet sequestration in rabbit pulmonary vasculature.26 Intratracheal PAF administration led to increased neutrophil infiltration, cell damage and hydrogen peroxide production of neutrophil-endothelial cell interface.27 The combined intravenous infusion of PAF and lipopolysaccharide (LPS) caused neutrophil aggregation, adhesion and accumulation into the lung parenchyma in anesthetized rats.28

PAF antagonists attenuated or prevented these changes.2,18,19,28 PAF-R knock-out also prevented exacerbation of leukocyte invasion by soybean oil.29 Exceptionally, one study indicated UK-74505 had no effect on neutrophil sequestration despite a substantial attenuation of lung injury.20 This may be explained by the specificity of its animal model.

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With initiation of inflammation in ARDS, inflammatory mediators are produced and released by leukocytes and endothelium. They enhance each other's production and function via positive feedback control mechanisms, forming a complicated mediator network and irreversible mediator cascades. The enhanced inflammatory mediators promote the activation and degranulation of leukocytes in turn, which results in release of more inflammatory mediators, and contribute to the formation of lung edema and pulmonary hypertension. PAF interacts with many other cytokines, chemokines and nuclear factors, stimulating their production, augmenting their effects, aggravating pulmonary inflammatory response and microcirculation disorder. Other factors affect PAF in turn.

Pre-incubation with tumor necrosis factor-α (TNF-α) dose-dependently increases both extracellular and intercellular PAF production in neutrophils from BALF of patients with ARDS.30 However, Chang et al31 found TNF-induced lung injury was not mediated by PAF. SM-12502 (a novel PAF antagonist) prevented increases in the serum concentration of TNF in a sepsis-induced ARDS rat model, and significantly inhibited the production of TNF-α by endothelin (ET)-stimulated monocytes in vitro.18 PAF-AH dose-dependently inhibited TNF production and its mRNA production of LPS-induced macrophages.32 It implies that PAF may increase production of TNF-α, thus PAF and TNF-α both can stimulate each other's production and form a positive feedback loop, which is important in the pathogenesis of pulmonary inflammation. Interleukin-1 (IL-1) also increased PAF activities in lungs of rats when given intratracheally.19 Like PAF, TNF-α and IL-1 also have been found in BALF and plasma of patients with ARDS.33,34 They can both produce a condition similar to ARDS when administered to rodents. So the interactions between them and PAF play a significant role in the development of ARDS.

PAF contributed to the release of mono-hydroxyeicosa-tetraenoic acids, one of which is the precursor of leukotriene in an endotoxin-induced lung injury model.35 In another study, PAF mediated IL-2-induced lung injury and contributed to the production of thromboxane B2 (TXB2).36 WEB2086 (another PAF antagonist) reduced the thromboxane synthesis and release after N-formyl-methionyl-leucyl-phenylalanine administration in in vivo endotoxin-primed lungs.37 Polyinosinic-poly cytidylic acid protected against PAF-induced responses in isolated perfused rabbit lungs, most likely via its induction of interferons. This effect is explained in part by interferons' inhibition of thromboxane A2 (TXA2) production stimulated by PAF.4 Besides, PAF-AH pretreatment had a dose-response inhibition of IL-8 and prostaglandin E2 (PGE2) production from LPS-induced macrophages.32 IL-6 had synergistic effect with PAF in priming PMN from human in vitro.25 PGE2 has been shown to mediate PAF-induced alterations in vascular permeability,38 which lead to formation of lung edema. TXA2 and leukotrienes are responsible for PAF-induced vasoconstriction in experimental studies,39-41 which participates the development of pulmonary hypertension. Thus PAF plays a critical role in the inflammatory mediator network.

PAF increased lung nuclear factor-κB (NF-κB) activation when given intratracheally to rats.27 Transfection of NF-κB decoy oligodeoxynucleotides also inhibited sepsis-incuced gene overexpression of PAF-R, acting as competitor for NF-κB's ability to bind to cognate recognition sequence.42 This proves that NF-κB can upregulate the expression of PAF-R. Increased PAF acts on its receptor, upregulated PAF-R, augmenting its transmembrane signal and biological effects, promoting the development of ARDS.

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Pulmonary edema may actually contribute to the pathogenesis of ARDS. The formation of protein-rich alveolar edema directly causes refractory hypoxemia and is considered as important physiopathologic basis for ARDS.

As the condition develops, activated leukocytes migrate into the pulmonary interstitium and damage alveolar region. Increased endothelial permeability leads to tissue edema.43,44 Diffuse damage to the alveolar region occurs in the acute or exudative phase of ARDS. This damage involves both the endothelial and epithelial surfaces and disrupts the lung's barrier function, flooding alveolar spaces with fluid, inactivating surfactant, causing inflammation, and producing severe gas exchange abnormalities and loss of lung compliance.

PAF can quickly raise vascular permeability in the pulmonary circulation and contribute to the development of lung edema. It has been found that PAF increased pulmonary microvascular permeability and induced pulmonary edema when given in picomolar doses to dogs45 and in nmol to isolated perfused rat lungs.46 Huang et al4 also found that perfusion of an isolated lung preparation with PAF increased lung weight gain.

Rabbit lungs exposed to LPS developed significant lung edema when stimulated with PAF.47 The combined administration of PAF and LPS also caused pulmonary edema in anesthetized rats.28 Repeated LPS-PAF stimulus caused alveolar proteinaceous exudates and progressive lung injury reminiscent of ARDS.48

Several studies indicated that PAF antagonists ameliorated the increase in extravascular lung water, decreased lung water content, prevented increases in pulmonary vascular permeability, and reduced the Evans blue dye content of lungs in animal models.18,20,37,49,50

The mechanisms of PAF in the development of lung edema is not clear. However, two possible mechanisms have been proposed: activation of the cyclooxygenase pathway and acid sphingomyelinase (ASM)-dependent production of ceramide. It has been demonstrated that the cyclooxygenase metabolite mediating PAF-induced increase in vascular permeability is PGE2.38 The another pathway, ASM-dependent production of ceramide was shown recently51 and worthy of further research. Mitogen-activated protein kinases has been involved in the regulation of PAF-induced hyperpermeability.52

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Pulmonary hypertension (PH) has been confirmed in large cohorts of patients with ARDS53 and widely recognised as a characteristic feature of ARDS. PH contributes to impaired right ventricular performance and cardiac output in ARDS patients, leading to a reduction in systemic oxygen delivery. The magnitude of PH has been shown to correlate with the severity of lung injury. Thus, resolution of ARDS is accompanied by an improvement in PH, whereas progressive PH has been shown to be associated with a poor outcome.54

PAF's pressor response is an important direct cause of PH, which is due to vasoconstriction and occlusion of the pulmonary microvasculature. PAF increased pulmonary artery pressure (Ppa) in an isolated perfused lung preparation, which was associated with increased TXB2 and decreased leukotriene production.4 However, in another isolated rat lung model, PAF in perfused solution significantly blunted angiotensin II-induced and hypoxic pulmonary vasoconstriction and PAF delivered as i.e. bolus injections caused acute vasodilation in preparations preconstricted with angiotensin II.55 An in vivo study found attenuation of hypoxic pulmonary vasoconstriction (HPV) by bleomycin-induced lung injury was not significantly affected by PAF antagonists WEB2170 and WEB2086, which means PAF does not mediate the loss of HPV in ARDS.56

In some studies, all the endotoxin-induced ARDS animal models had increased Ppa or pulmonary vascular resistance. These changes were attenuated or abrogated by some PAF antagonists or PAF-R knock-out57 but not by other antagonists.49,58

The exact mechanism of PAF in PH is not well understood. It was found that PAF stimulated lung pericyte growth in vitro and did not induce apoptosis in pericytes.59 Proliferation of pericytes leads to muscularization of pulmonary vessel walls and thus may contribute to the development of PH in late phase of ARDS.

In the past several decades, the molecular pathophysiology of ARDS and the role of PAF in ARDS has been better understood. Therefore, PAF represents an attractive target in ARDS. Further studies about the actions of PAF in ARDS may lead to a new therapy which reduces morbidity and mortality of ARDS. However, because of the inaccessibility of human lung and the difficulties in obtaining histological samples in humans, until now most of our knowledge of the pathophysiology of the disease comes from experimental studies. So it is important to notice the differences between human and animals in research.

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acute respiratory distress syndrome; platelet activating factor

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