Secretory Phospholipase A2-Mediated Depletion of Phosphatidylglycerol in Early Acute Respiratory Distress Syndrome

Abstract

Background Secretory phospholipases A2 (sPLA2) hydrolyze phospholipids in cell membranes and extracellular structures such as pulmonary surfactant. This study tests the hypothesis that sPLA2 are elevated in human lungs during acute respiratory distress syndrome (ARDS) and that sPLA2 levels are associated with surfactant injury by hydrolysis of surfactant phospholipids. Methods Bronchoalveolar lavage (BAL) fluid was obtained from 18 patients with early ARDS (<72 hours) and compared to samples from 10 healthy volunteers. Secreted phospholipase A2 were measured (enzyme activity and enzyme immunoassay) in conjunction with ARDS subjects’ surfactant abnormalities including surfactant phospholipid composition, large and small aggregates distribution, and surface tension function. Results BAL sPLA2 enzyme activity was markedly elevated in ARDS samples relative to healthy subjects when measured by ex vivo hydrolysis of both phosphatidylglycerol (PG) and phosphatidylcholine (PC). Enzyme immunoassay identified increased PLA2G2A protein in the ARDS BAL fluid, which was strongly correlated with the sPLA2 enzyme activity against PG. Of particular interest, we demonstrated an average depletion of 69% of the PG in the ARDS sample large aggregates relative to the normal controls. Furthermore, the sPLA2 enzyme activity against PG and PC ex vivo correlated with the BAL recovery of in vivo PG and PC, respectively, and also correlated with the altered distribution of the large and small surfactant aggregates. Conclusions These results support the hypothesis that sPLA2-mediated hydrolysis of surfactant phospholipid, especially PG by PLA2G2A, contributes to surfactant injury during early ARDS.

Decreased surfactant lipids correlate with lung function in chronic obstructive pulmonary disease (COPD)

“…BMP is specific of lysosomal inner membranes and its presence in BAL could originate from the exocytosis of lamellar bodies, which are lysosome-related organelles. Alternatively, enhanced extracellular PLA 2 activity and subsequent catabolism of PL to LPL, which is associated with inflammation, could further explain the decreased surfactant PL in COPD patients [31,32]. We did not find significantly increased LPL/PL ratios in COPD ( S2 Fig), but LPL have a short life and do not accumulate, challenging their accurate detection.…”

Veno-venous ECMO as a platform to evaluate lung lavage and surfactant replacement therapy in an animal model of severe ARDS

“…Perhaps performing the lavage with surfactant itself, as suggested by the results in a lung contusion model of ARDS [ 17 ], could take advantage of its adsorption properties and facilitate distribution and subsequent recovery. However, even exogenous surfactant could have been degraded by the activity of specific enzymes, including the secretory phospholipase A2 [ 27 ], which in patients with direct forms of ARDS has been shown to inversely correlate with PaO 2 /FiO 2 ratio and mortality [ 28 ]. Alternatively, it is possible that lung lavage itself had worsened the injury in the peripheral, ventilated alveolar units, increasing lung consolidation and preventing alveolar delivery of surfactant, or increasing the air–water surface tension, which is recognized as one of the mechanisms of cellular damage and lung injury propagation [ 29 ].…”

The Contribution of Surface Tension-Dependent Alveolar Septal Stress Concentrations to Ventilation-Induced Lung Injury in the Acute Respiratory Distress Syndrome

“…Inflammatory cells release secretory phospholipase A 2 and certain bacteria, including Pseudomonas, release phospholipase C (Holm et al, 1991;Kitsiouli et al, 2009). Accordingly, in BALF from ARDS patients, elevated phospholipase levels and activity have been observed (Hallman et al, 1982;Seeds et al, 2012). Phospholipases could elevate T directly, by reducing the availability of T-lowering surfactant phospholipids.…”