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

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 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.

Results: 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.

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.