Role of Lung-marginated Monocytes in an In Vivo Mouse Model of Ventilator-induced Lung Injury

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Abstract
Rationale: Recruited leukocytes play an important role in ventilator-induced lung injury, although studies have focused predominantly on neutrophils. Inflammatory subset Gr-1high monocytes are recruited to sites of inflammation and have been implicated in acute lung injury induced by systemic endotoxin. Objectives: To investigate the recruitment and role of Gr-1high monocytes in an in vivo mouse model of ventilator-induced lung injury. Methods: Anesthetized mice were ventilated with low or high stretch. Flow cytometry was used to quantify monocyte subset margination to the lungs, and to assess their in situ cellular activation in response to mechanical stretch. To investigate monocyte involvement in lung injury progression, a two-hit model was used, with a subclinical dose of lipopolysaccharide (intraperitoneal) given 2 hours prior to high-stretch ventilation. In some animals, monocytes were depleted using intravenous clodronate liposomes. Development of lung injury was assessed in ventilated animals by peak inspiratory pressure and respiratory system mechanics. Measurements and Main Results: High-stretch ventilation induced significant pulmonary margination of Gr-1high but not Gr-1low monocytes compared with nonventilated mice. These monocytes displayed increased activation status, with higher CD11b (vs. nonventilated mice) and lower L-selectin expression (vs. low-stretch ventilation). Lipopolysaccharide challenge led to enhanced lung margination of Gr-1high monocytes and neutrophils, and sensitized the lungs to high stretch–induced pulmonary edema. Clodronate-liposome pretreatment depleted lung monocytes (but not neutrophils) and significantly attenuated lung injury. Conclusions: High-stretch mechanical ventilation promotes pulmonary margination of activated Gr-1high monocytes, which play a role in the progression of ventilator-induced lung injury.