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.
Highlights
Mechanical ventilation is required for patients that suffer from acute respiratory failure or acute respiratory distress syndrome (ARDS), which can be triggered by direct pulmonary insult and indirect extra-pulmonary insult [1]
Using celecoxib, which is a COX-2-specific inhibitor, we demonstrated that COX-2 activity is important in mediating the recruitment of vascular endothelial growth factor (VEGF)-secreting Ly6Chigh monocytes that contribute to the increase of total protein in bronchoalveolar lavage fluid (BALF) during the development of ventilator-induced lung injury (VILI)
To investigate the effect of the COX-2 pathway in VILI, our previously established murine model of VILI [13], which consisted of intraperitoneal administration of celecoxib (20 or 40 mg/kg) 1 h prior to high tidal volume (HTV)-mechanical ventilation, was used
Summary
Mechanical ventilation is required for patients that suffer from acute respiratory failure or acute respiratory distress syndrome (ARDS), which can be triggered by direct pulmonary insult and indirect extra-pulmonary insult [1]. The recruitment of inflammatory leukocytes, alveolar macrophages [8] and neutrophils [9,10], which migrate to the pulmonary microenvironment and release inflammatory and injurious mediators, plays a critical role in the pathogenesis of VILI [4]. Ly6ChighCCR2highCX3CR1low monocytes, which express high levels of Ly6C (Ly6Chigh) and C-C chemokine receptor 2 (CCR2high) and low levels of CX3C chemokine receptor 1 (CX3CR1low), are designated as the inflammatory subset, and they are derived from bone marrow macrophage-dendritic precursor cells that migrate to inflammatory sites during injury [14,15]. Studies have reported that the rapid recruitment of monocytes, the Ly6Chigh subset, to the lung microvasculature, contributes to pulmonary-vascular injury in a murine model of systemic endotoxemia [17,18]
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