Cyclooxygenase-2 Activity Regulates Recruitment of VEGF-Secreting Ly6Chigh Monocytes in Ventilator-Induced Lung Injury

Abstract

Mechanical ventilation is usually required for saving lives in critically ill patients; however, it can cause ventilator-induced lung injury (VILI). As VEGF-secreting Ly6Chigh monocytes are involved in VILI pathogenesis, we investigated whether cyclooxygenase-2 (COX-2) activity regulates the recruitment of VEGF-secreting Ly6Chigh 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 Ly6Chigh 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 Ly6Chigh, but not Ly6Clow, monocytes. Celecoxib significantly diminished the recruitment of Ly6Chigh 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 Ly6Chigh monocytes, which are involved in VILI pathogenesis, and indicate that the suppression of COX-2 activity might be a useful strategy in mitigating VILI.

Mining the key genes for ventilator-induced lung injury using co-expression network analysis

“…Tzu-Hsiung Huang et al used the COX-2 inhibitor celecoxib to intervene in a mouse model of VILI, and detected the pulmonary vascular permeability and leakage, inflammatory leukocyte infiltration, and pulmonary oxygenation to assess the severity of VILI [41]. It revealed that the celecoxib-intervened VILI mice model exhibited a significant decrease in the associated indices compared with the control [41]. In another study, Fan-you Meng et al constructed a VILI mice model by injecting endotoxin to induce ARDS, followed by mechanical ventilation [42].…”

“…Back in 1991, Xie et al [ 39 ] and Kujubu et al [ 40 ], respectively, discovered in their studies an mRNA encoding protein and a cDNA encoding protein, which were proved later to be the same enzyme; it is highly expressed in inflammatory cells when activated, and is named as COX-2, an isozyme of already known COX-1. Huang et al used the COX-2 inhibitor celecoxib to intervene in a mouse model of VILI, and detected the pulmonary vascular permeability and leakage, inflammatory leukocyte infiltration and pulmonary oxygenation to assess the severity of VILI [ 41 ]. It revealed that the celecoxib-intervened VILI mice model exhibited a significant decrease in the associated indices compared with the control [ 41 ].…”

Significance of Pulmonary Endothelial Injury and the Role of Cyclooxygenase-2 and Prostanoid Signaling

“…Many studies show overexpression of COX-2 and the resulting increased production of prostanoids during an inflammatory reaction in the lung, usually focusing on lung epithelial cells [171], fibroblasts, or inflammatory cells [172] (reviewed in [173][174][175][176]). For example, in a rat model of meconium aspiration, COX-2 expression has been induced in the respiratory epithelium and in alveolar macrophages [177].…”