Phospholipases A2 as biomarkers in acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a multifactorial life-threatening lung injury, characterized by diffuse lung inflammation and increased alveolocapillary barrier permeability. The different stages of ARDS have distinctive biochemical and clinical profiles. Despite the progress of our understanding on ARDS pathobiology, the mechanisms underlying its pathogenesis are still obscure. Herein, we review the existing literature about the implications of phospholipases 2 (PLA2s), a large family of enzymes that catalyze the hydrolysis of fatty acids at the sn-2 position of glycerophospholipids, in ARDS-related pathology. We emphasize on the versatile way of participation of different PLA2s isoforms in the distinct ARDS subgroup phenotypes by either potentiating lung inflammation and damage or by preserving the normal lung. Current research supports that PLA2s are associated with the progression and the outcome of ARDS. We herein discuss the transcellular communication of PLA2s through secreted extracellular vesicles and suggest it as a new mechanism of PLA2s involvement in ARDS. Thus, the elucidation of the spatiotemporal features of PLA2s expression may give new insights and provide valuable information about the risk of an individual to develop ARDS or advance to more severe stages, and potentially identify PLA2 isoforms as biomarkers and target for pharmacological intervention.

Keywords: ARDS; Biomarkers; Extracellular vesicles; Phospholipases 2; Sepsis.

Fig. 1

Phospholipases A2 in ARDS. Normal alveolus (Panel A). In the normal alveoli the epithelium is intact. Alveolar Type I cells permit gas exchange, while Alveolar Type II cells produce lung surfactant. Resident alveolar macrophages under normal conditions express protein levels of cPLA2-IVA and aiPLA2 but not sPLA2IIA. EVs contain sPLA2IIA mRNA but not sPLA2IIA as a functional protein. Alveolus in early phase of ARDS (Panel B). Alveolar-capillary damage leads in alveoli flooding with a proteinaceous liquid (blue color). Activated alveolar macrophages and recruited monocytes and neutrophils (NP) from the circulation secrete sPLA2IIA and extracellular traps which participate in the clearance of microbial intruders. At the same time, sPLA2IIA can deteriorate lung surfactant. Lyso-PC, PAF and eicosanoids production is an on-going process at this stage of ARDS. sPLA2V and sPLA2IIA are linked with epithelial and endothelial damage. EVs1 containing sPLA2IIA at both mRNA and protein levels, as well as pcPLA2 are secreted into the extracellular space. EVs containing sPLA2IIA mediate transcellular communication locally or in distal locations. Alveolus in late phase of ARDS (Panel C). A proliferative phase follows the early phase of ARDS during which repairment procedures and proliferation of fibroblasts is taking place. Finally, a fibrotic phase may ensue contributing to chronic inflammation. Lyso-PC levels are yet detectable at this phase. EVs contain sPLA2IIA mRNA but not sPLA2IIA as a functional protein.