Paracoxib Alleviates Ventilator-Induced Lung Injury Through Functional Modulation of Lung-Recruited CD11bloLy6Chi Monocytes

Chaofeng Zhang, Shanshan Hu, Graeme R Zosky, Xin Wei, Shuhua Shu, Di Wang, Xiaoqing Chai
Shock 2020 June 23

OBJECTIVE: Lung-recruited Ly6C monocytes had been shown to be involved in ventilator-induced lung injury (VILI). Our present study aimed to investigate whether the COX-2 inhibition modulates the function of lung-recruited Ly6C monocytes in a mouse model of VILI.

METHODS: Mice were exposed to lipopolysaccharide (LPS; 20 ng) intraperitoneally prior to injurious mechanical ventilation (Vt = 30 ml/kg, PEEP = 0 cmH2O). A subgroup of mice was treated with intravenous parecoxib (30 mg/kg), a COX-2 inhibitor, 1 hour prior to ventilation. Control mice received saline and were not ventilated. At the end of the experiment, blood gas analysis was performed and lung tissue was collected for histological assessment. Flow cytometry was employed to quantify the different populations of lung monocytes/macrophages and their function. Isolated Ly6C cells were used to measure the intracellular concentrations of reactive oxygen species (ROS) and nitric oxide (NO) by fluorescent probes, and cytokine production by cytometric bead array.

RESULTS: Exposure to LPS and injurious ventilation was associated with severe lung histological damage, oxygenation impairment, and pulmonary edema; all of which were largely attenuated following the treatment of parecoxib. Furthermore, flow cytometry analysis revealed that parecoxib caused a reduction in the number of the lung-recruited CD11bLy6C monocytes while there was no effect on tissue-resident CD64 alveolar macrophages. In addition, the production of oxidative stress products (ROS, NO), MHC-II expression and inflammatory cytokines in response to LPS and VILI in CD11bLy6C monocytes was ameliorated by parecoxib.

CONCLUSION: Parecoxib-induced alleviation of oxidative stress and inflammation in lung-recruited Ly6C monocytes may partly explain the beneficial action of COX-2 inhibition in VILI.

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