Elevated Plasma Levels of Gas6 Are Associated with Acute Lung Injury in Patients with Severe Sepsis

Abstract

Acute lung injury (ALI) is one of the complications of severe sepsis, causing sudden deaths. However, information regarding predictive factors for the onset of ALI in severe sepsis is limited. Growth arrestspecific gene 6 (Gas6) is secreted by endothelial cells and is important for the activation of endothelium during inflammation. This study aimed to investigate the predictive effect of plasma Gas6 in patients with severe sepsis. Collection of plasma samples was carried out from 129 participants with severe sepsis following with or without ALI development. We found that the elevated levels of Gas6, interleukin-6 and -8 (IL-6 and IL-8) in plasma were associated with the ALI development (P = 0.003, 0.002, and 0.004, respectively). We also observed the robust correlation between the plasma level of Gas6 and the following ALI development to adjustment for sepsis and administration of vasopressor. Between patients with ALI (n = 18) and those without ALI (n = 111), Gas6 and the Lung Injury Prediction Score (LIPS) showed promising discrimination (AUROC, 0.74 and 0.68, respectively), and in combination with these two indexes, the AUROC was increased to 0.86 (vs. 0.74, P = 0.05), while soluble receptor for advanced glycation end products (sRAGE) and Willebrand factor (vWF) in plasma showed no predictive value for of ALI. Collectively, our findings indicate that higher levels of Gas6 in plasma are obviously correlated with ALI development. An early increase in the plasma Gas6 level suggests that endothelial injury is a key link in the pathogenesis of ALI.

Gas6/TAM Axis in Sepsis: Time to Consider Its Potential Role as a Therapeutic Target

“…Thus, Gas6 levels were associated with disease severity and organ dysfunction. New studies have been conducted on a cohort of septic patients diagnosed following the Sepsis-3 criteria [101, 102]. In a cohort of 129 patients, it was reported that Gas6 plasmatic levels at admission in an intensive care unit (ICU) were higher in nonsurvivors than survivors [101].…”

“…According to these findings, Gas6 cannot predict sepsis evolution, unlike other inflammatory mediators, such as TNF- α and IL-1 β [101]. The role of Gas6 in septic patients was recently highlighted also in sepsis-related acute lung injury (ALI) by Yeh et al [102]. Indeed, ALI is one of the complications of sepsis, and it is known for its contribution to sudden deaths and morbidity [103].…”

“…Since nowadays a prompt and correct ALI diagnosis is mandatory in order to develop an effective treatment, the authors suggested Gas6 as an early predictor of ALI. Moreover, they suggested that Gas6 could also improve the parameters of the lung injury prediction score, such as its discrimination and its positive and negative predictive values [102].…”

Markers of NETosis and DAMPs are altered in critically ill COVID-19 patients

“…The components of the GAS6/TAM system have been shown to increase in a diverse spectrum of in ammatory conditions [52], including sepsis and septic shock; but also systemic in ammatory response syndrome (SIRS) without infection [53]. In several studies, GAS6 concentration in plasma at IC admission correlated with severity of organ damage, either in SOFA or with damage of speci c organs [53][54][55][56][57]. This also the case in viral infections.…”

Gas6 Attenuates Sepsis-Induced Tight Junction Injury and Vascular Endothelial Hyperpermeability via the Axl/NF-κB Signaling Pathway

“…In fact, many studies have investigated the effect of Gas6 on sepsis. Gas6 was present at high levels in plasma during sepsis and correlated well with organ dysfunction (Borgel et al, 2006; Gibot et al, 2007; Ekman et al, 2010; Yeh et al, 2017). In line with our findings ( Figure 1 ), some studies have shown that Gas6 can effectively reduce organ injury in sepsis (Giangola et al, 2013; Chen et al, 2016).…”