Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney

Abstract

In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared-mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.

Keywords: lung-kidney crosstalk.

Fig. 1.

Proteome array analysis of inflammatory mediator levels in different injury models. Pooled kidney tissue lysates from mice exposed to Sham operation, cecal ligation and puncture (CLP), ventilator induced lung injury (VILI), and CLP+VILI (n = 4 for each group) were evaluated by Mouse XL cytokine array (R&D Systems). Relative expression of 111 different mediators are shown relative to Sham. Mediators with higher levels in VILI and VILI+CLP groups compared with CLP and Sham are highlighted in yellow. Mediators with twofold increases with dual injury (CLP+VILI) are highlighted in red.

Fig. 2.

Renal VCAM-1, VEGF, and endostatin levels following VILI, CLP, or CLP+VILI. In kidney homogenates, protein levels of VCAM-1, VEGF, and endostatin were determined by Western blot analysis. All groups were run on the same gel. n = 4 mice for each group. VCAM-1 level in CLP+VILI vs. CLP (P = 0.08). (*P < 0.05, **P < 0.01, ***P < 0.001).

Fig. 3.

Renal angiopoietin-2 levels following VILI, CLP, or CLP+VILI. In total kidney homogenates, angiopoietin-2 levels were determined by ELISA. n = 4 mice for each group. ***P < 0.001).

Fig. 4.

Neutrophil gelatinase-associated lipocalin (NGAL) levels in renal tissue following VILI, CLP, or CLP+VILI. In total kidney homogenates, NGAL levels were determined by Western blot analysis. All groups were run on the same gel. n = 3 mice for each group. **P < 0.01, ***P < 0.001).