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

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.

Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low V_T) or moderate (10 mL/kg; mod V_T) 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 V_T. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined.

VILI was characterized by reduced PaO₂/FiO₂ ratio (low V_T: 540 [381–661] vs. control: 693 [620–754], p < 0.05), increased wet-to-dry weight ratio (low V_T: 4.8 [4.6–4.9] vs. control: 4.5 [4.4–4.6], p < 0.05), pneumonia (low V_T: 30 [0–58] vs. control: 0 [0–0]%, p < 0.05) and interstitial inflammation (low V_T: 2 [1–3] vs. control: 1 [0–1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod V_T + FG-3154: 4.8 [4.7–5.0] vs. mod V_T + vehicle: 4.8 [4.8–5.0], p > 0.99), extravasated dextrans (mod V_T + FG-3154: 0.06 [0.04–0.09] vs. mod V_T + vehicle: 0.04 [0.03–0.09] µg/mg tissue, p > 0.99), sRAGE (mod V_T + FG-3154: 1865 [1628–2252] vs. mod V_T + vehicle: 1885 [1695–2159] pg/mL, p > 0.99) or histopathology.

‘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.