Induction of type-IIA secretory phospholipase A2 in animal models of acute lung injury

Abstract

The aim of this study was to evaluate the presence of type-II secretory phospholipase A2 (sPLA2-IIA) in alveolar space and its possible role in the destruction of surfactant in three rat models of acute lung injury.Alveolar instillation of either lipopolysaccaride or live Pseudomonas aeruginosa resulted in a significant increase in lung oedema and in a decrease in static compliance of the respiratory system together with alveolar-neutrophil influx as compared with healthy control rats.The upregulation of messenger ribonucleic acid and sPLA2-IIA by the lung was evident. This was associated with surfactant degradation and a decrease in large:small ratio of surfactant aggregates in bacteria-instilled rats. A negative correlation between compliance and sPLA2-IIA activity in bronchoalveolar lavage fluid was shown. By contrast, during alpha naphthylthiourea-induced injury, neither alveolar-neutrophil influx nor increase in sPLA2-IIA activity was observed.Additional experiments in rats treated with a specific inhibitor of type-II secretory phospholipase A2 activity (3 acetamine-1-benzyl-2 ethylindolyl-5 oxy; propane phosphonic acid (LY311727)) demonstrated no improvement in physiological parameters despite a biochemical effect, suggesting that its activity is only one of the multiple factors involved in the pathophysiology of lung injury. Surfactant degradation has been shown to be one of the key features of acute respiratory distress syndrome (ARDS) leading to a decrease in both lung compliance and oxygenation [1,2]. Consequently, several clinical trials have evaluated the effect of exogenous surfactant administration. However, the relative inefficacy of this approach has been attributed to insufficient alveolar delivery of exogenous surfactant and/or to its inhibition/degradation by alveolar enzymatic activities [2]. Along this line, type-IIA secretory phospholipase A2 (sPLA2-IIA), an enzyme produced by alveolar inflammatory cells during acute lung injury (ALI), has previously been shown to participate in surfactant degradation [3][4][5]. sPLA2-IIA belongs to a superfamily of enzymes that hydrolyses the sn-2 fatty acyl ester bond of phosphoglycerides, generating lysophospholipids and free fatty acids [6]. These enzymes play a major role in the induction of inflammatory reactions via the synthesis of lipid mediators, such as platelet activating factor, leukotrienes and prostaglandins [5,6]. A number of studies suggest that sPLA2-IIA is involved in the pathogenesis of inflammatory diseases including ARDS. Indeed, a clinical trial demonstrated an increased sPLA2-IIA activity in bronchoalveolar lavage (BAL) fluid of patients with ARDS whose levels were positively correlated with disease severity [5].The assessment of the role of sPLA2-IIA activity in terms of both surfactant and compliance impairment is of major value, since its inhibition could constitute a therapeutic approach. Therefore, the aims of this study were to assess whether correlation could be established between indexes of injury (lung oedema, art...

Animal models of hospital-acquired pneumonia: current practices and future perspectives

“…Intratracheal instillation is the most used method in HAP research and involves injecting the bacterial suspension directly into the trachea or lungs followed by air for dispersion of the bolus (33,(43)(44)(45)(46)(47)(48)(49)(50). This method gives the most precise control on the delivered dose.…”

Surfactant for Pediatric Acute Lung Injury

“…However, synthetic ether-linked lipids are now available that have direct structural analogy to lung surfactant lipids plus designed molecular behavior that enhances adsorption and spreading while maintaining very high dynamic surface tension lowering in surface films (e.g., [71,[205][206][207][208][209][210][211]). Moreover, such lipids have structural features making them resistant to phospholipases such as phospholipase A 2 , which has been implicated in the pathology of ALI/ARDS [65,[212][213][214][215][216][217][218]. Phospholipase-induced degradation of lung surfactant glycerophospholipids not only reduces the concentration of active components, but also generates reaction products such as lysophosphatidylcholine and fluid free fatty acids that can further decrease surface activity by interacting biophysically with remaining surfactant at the alveolar interface [55,59,70].…”

Proapoptotic effects of P. aeruginosa involve inhibition of surfactant phosphatidylcholine synthesis

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