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. 2019 Apr 10;20(7):1771.
doi: 10.3390/ijms20071771.

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

Tzu-Hsiung Huang  1   2 , Pin-Hui Fang  3 , Jhy-Ming Li  4   5 , Huan-Yuan Ling  6 , Chieh-Mo Lin  7   8   9 , Chung-Sheng Shi  10   11   12
Affiliations

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

Tzu-Hsiung Huang et al. Int J Mol Sci. .

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.

Keywords: Ly6Chigh monocytes; cyclooxygenase-2; ventilator-induced lung injury.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Celecoxib attenuated ventilator-induced lung injury (VILI) and decreased the infiltration of leukocytes in BALF during VILI. (A) Representative micrographs of hematoxylin-and-eosin-stained sections of the lung. Scale bar = 100 μm. (B) Cytological analyses of mononuclear cells and polymorphonuclear neutrophils (PMN) in bronchoalveolar lavage fluid (BALF). Values represent the mean ± SD (n = 6). # p < 0.05 and * p < 0.01, when compared with the control or between groups.
Figure 2
Figure 2
Cyclooxygenase-2 (COX-2)-expressing Ly6Chigh monocytes recruited into the lung during VILI. (A,B) Gating strategy of flow cytometry analysis. (C) Time course recruitment of COX-2-expressing Ly6Chigh monocytes, Ly6Clow monocytes, and neutrophils during VILI. Values represent the mean ± SD (n = 6). * p < 0.01 as compared with the control at that time point.
Figure 3
Figure 3
Celecoxib significantly diminished the recruitment of Ly6Chigh, but not Ly6Clow, monocytes in VILI. (A) Gating strategy of flow cytometry analysis. (B) The numbers of Ly6C monocytes in lung homogenates. Values represent the mean ± SD (n = 6). # p < 0.05 and * p < 0.01, when compared with the control or between groups.
Figure 4
Figure 4
Celecoxib significantly reduced pulmonary-vasculature permeability and improved pulmonary oxygenation in VILI. (A) BALF total protein. (B) BALF vascular endothelial growth factor (VEGF). (C) PaO2/FiO2. Values represent the mean ± SD (n = 6). # p < 0.05 and * p < 0.01, as compared with the control or between groups.
Figure 5
Figure 5
The secretion of VEGF by sorted Ly6Chigh monocytes was COX-2-dependent. Values represent the mean ± SD (n = 4). * p < 0.01 compared to individual group of 1 h or compared with group untreated with celecoxib.
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