Biomarkers of alveolar epithelial injury and endothelial dysfunction are associated with scores of pulmonary edema in invasively ventilated patients

Abstract

Pulmonary edema is a central hallmark of acute respiratory distress syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to alveolar-capillary permeability but their differential contribution to pulmonary edema development remains understudied. Plasma levels of surfactant protein-D (SP-D), soluble receptor for advanced glycation end products (sRAGE), and angiopoietin-2 (Ang-2) were measured in a prospective, multicenter cohort of invasively ventilated patients. Pulmonary edema was quantified using the radiographic assessment of lung edema (RALE) and global lung ultrasound (LUS) score. Variables were collected within 48 h after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. In 362 patients, higher SP-D, sRAGE, and Ang-2 concentrations were significantly associated with higher RALE and global LUS scores. After stratification by ARDS subgroups (pulmonary, nonpulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, whereas sRAGE and Ang-2 showed less consistent associations throughout the subgroups. In a multivariable analysis, SP-D levels were most strongly associated with pulmonary edema when combined with sRAGE (RALE score: β_SP-D = 6.79 units/log10 pg/mL, β_sRAGE = 3.84 units/log10 pg/mL, R² = 0.23; global LUS score: β_SP-D = 3.28 units/log10 pg/mL, β_sRAGE = 2.06 units/log10 pg/mL, R² = 0.086), whereas Ang-2 did not further improve the model. Biomarkers of epithelial injury and endothelial dysfunction were associated with pulmonary edema in invasively ventilated patients. SP-D and sRAGE showed the strongest association, suggesting that epithelial injury may form a final common pathway in the alveolar-capillary barrier dysfunction underlying pulmonary edema.

Keywords: ARDS; endothelial dysfunction; epithelial injury; pulmonary edema; vascular permeability.

Graphical abstract

Figure 1.

Association of plasma biomarkers [surfactant protein (SP)-D, soluble receptor for advanced glycation end products (sRAGE), and angiopoietin (Ang)-2] with the radiographic assessment of lung edema (RALE) score (A) and the global lung ultrasound (LUS) score (B) in the total population (n = 362). Increases in surfactant protein (SP)-D, soluble receptor for advanced glycation end products (sRAGE), and angiopoietin (Ang)-2 were all significantly associated with an increase of the RALE score [β_SP-D (95% CI) = 8.4 units/log10 pg/mL (6.4–10.4), β_sRAGE (95% CI) = 6.8 units/log10 pg/mL (4.7–8.9), β_Ang-2 (95% CI) = 3.9 units/log10 pg/mL (1.7–6.1), all P < 0.001] and the global LUS score [β_SP-D (95% CI) = 4.3 units/log10 pg/mL (2.6–5.9), β_sRAGE (95% CI) = 3.5 units/log10 pg/mL (1.9–5.1), β_Ang-2 (95% CI) = 1.6 units/log10 pg/mL (0.02–3.2), all P < 0.05]. Plasma biomarkers are represented as units/log10 pg/mL.

Figure 2.

Association of surfactant protein (SP)-D (A), soluble receptor for advanced glycation end products (sRAGE; B), and angiopoietin (Ang)-2 (C) with the radiographic assessment of lung edema (RALE) score. Statically significant associations of the predictors with the RALE score: SP-D: in patients with and without ARDS [β (95% CI) = 8.17 units/log10 pg/mL (5.36–10.99) and 4.97 units/log10 pg/mL (2.49–7.46), both P < 0.001], COVID and non-COVID ARDS [β (95% CI) = 10.63 units/log10 pg/mL (3.52–17.73), P = 0.004 and 8.23 units/log10 pg/mL (5.07–11.39), P < 0.001], and pulmonary and nonpulmonary ARDS [β (95% CI) = 7.83 units/log10 pg/mL (3.98–11.69), P < 0.001 and 4.96 units/log10 pg/mL (0.42–9.50), P = 0.04]. sRAGE: in patients with and without ARDS [β (95% CI) = 6.50 units/log10 pg/mL (3.21–9.78) and 5.62 units/log10 pg/mL (3.44–7.80), both P < 0.001], COVID and non-COVID ARDS [β (95% CI) = 7.59 units/log10 pg/mL (1.33–13.84), P = 0.017 and 5.93 units/log10 pg/mL (2.04–9.82), P = 0.004], and pulmonary ARDS [β (95% CI) = 6.18 units/log10 pg/mL (2.23–10.13), P = 0.003]. Ang-2: in patients without ARDS [β (95% CI) = 6.19 units/log10 pg/mL (4.09–8.28), P < 0.001]. Tested associations did not reach statistical significance in the other subgroups. Plasma biomarkers are represented as units/log10 pg/mL. ARDS, acute respiratory distress syndrome.

Figure 3.

Association of surfactant protein (SP)-D (A), soluble receptor for advanced glycation end products (sRAGE; B), and angiopoietin (Ang)-2 (C) with the global lung ultrasound (LUS) score. Statically significant associations of the predictors with the global LUS score: SP-D: in patients without ARDS [β (95% CI) = 2.04 units/log10 pg/mL (0.13–3.95), P = 0.04] and in patients with pulmonary ARDS [β (95% CI) = 3.71 units/log10 pg/mL (0.40–7.02), P = 0.03]. sRAGE and Ang-2: in patients without ARDS [β (95% CI) = 4.15 units/log10 pg/mL (2.56–5.73) and 3.59 units/log10 pg/mL (2.14–5.04), respectively, both P < 0.001]. Tested associations did not reach statistical significance in the other subgroups. Plasma biomarkers are represented as units/log10 pg/mL. ARDS, acute respiratory distress syndrome.