Cyclooxygenase-2 Activity Regulates Recruitment of VEGF-Secreting Ly6C(high) Monocytes in Ventilator-Induced Lung Injury

Mechanical ventilation is usually required for saving lives in critically ill patients; however, it can cause ventilator-induced lung injury (VILI). As VEGF-secreting Ly6C(high) monocytes are involved in VILI pathogenesis, we investigated whether cyclooxygenase-2 (COX-2) activity regulates the recruitment of VEGF-secreting Ly6C(high) monocytes during VILI. The clinically relevant two-hit mouse model of VILI, which involves the intravenous injection of lipopolysaccharide prior to high tidal volume (HTV)-mechanical ventilation, was used in this study. To investigate the role of COX-2 in the recruitment of VEGF-secreting Ly6C(high) monocytes during VILI, celecoxib, which is a clinical COX-2 inhibitor, was administered 1 h prior to HTV-mechanical ventilation. Pulmonary vascular permeability and leakage, inflammatory leukocyte infiltration, and lung oxygenation levels were measured to assess the severity of VILI. HTV-mechanical ventilation significantly increased the recruitment of COX-2-expressing Ly6C(high), but not Ly6C(low), monocytes. Celecoxib significantly diminished the recruitment of Ly6C(high) monocytes, attenuated the levels of VEGF and total protein in bronchoalveolar lavage fluid, and restored pulmonary oxygenation during VILI. Our findings demonstrate that COX-2 activity is important in the recruitment of VEGF-secreting Ly6C(high) monocytes, which are involved in VILI pathogenesis, and indicate that the suppression of COX-2 activity might be a useful strategy in mitigating VILI.