Effect of antibody-mediated connective tissue growth factor neutralization on lung edema in ventilator-induced lung injury in rats

Abstract

Background Acute respiratory distress syndrome (ARDS) is characterized by alveolar edema that can progress to septal fibrosis. Mechanical ventilation can augment lung injury, termed ventilator-induced lung injury (VILI). Connective tissue growth factor (CTGF), a mediator of fibrosis, is increased in ARDS patients. Blocking CTGF inhibits fibrosis and possibly vascular leakage. This study investigated whether neutralizing CTGF reduces pulmonary edema in VILI. Methods Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low VT) or moderate (10 mL/kg; mod VT) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low VT. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined. Results VILI was characterized by reduced PaO2/FiO2 ratio (low VT: 540 [381–661] vs. control: 693 [620–754], p < 0.05), increased wet-to-dry weight ratio (low VT: 4.8 [4.6–4.9] vs. control: 4.5 [4.4–4.6], p < 0.05), pneumonia (low VT: 30 [0–58] vs. control: 0 [0–0]%, p < 0.05) and interstitial inflammation (low VT: 2 [1–3] vs. control: 1 [0–1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod VT + FG-3154: 4.8 [4.7–5.0] vs. mod VT + vehicle: 4.8 [4.8–5.0], p > 0.99), extravasated dextrans (mod VT + FG-3154: 0.06 [0.04–0.09] vs. mod VT + vehicle: 0.04 [0.03–0.09] µg/mg tissue, p > 0.99), sRAGE (mod VT + FG-3154: 1865 [1628–2252] vs. mod VT + vehicle: 1885 [1695–2159] pg/mL, p > 0.99) or histopathology. Conclusions ‘Double hit’ VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI. Graphical Abstract