Therapeutic Treatment with a Clinically Relevant Dose of Dexamethasone Reduces Pulmonary Vascular Leak in a Mouse Model of ARDS.

PURPOSE: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening acute lung injury with great unmet medical needs. Lung edema resulting from increased vascular leak is a hallmark of the disease. Recently corticosteroids were recommended for ARDS patients by the American Thoracic Society. Here, we use the influenza infection mouse model to study vascular leak induced by viral lung injury and the effect of dexamethasone on vascular leak and mortality.

METHODS

Near-infrared fluorescence (NIRF) imaging was used to quantitatively measure vascular leak in mice infected with influenza PR8, and the effect of dexamethasone was analyzed as a function of dose and time of the treatment.

RESULTS

NIRF imaging robustly detects vascular leak up to 14 days post-infection. Dexamethasone treatment reduces mortality and vascular leak when administered on day 9 post infection, corresponding to the time of influenza virus clearance. Early treatment of dexamethasone, either prophylactically or on day 5 post infection, has a negative impact on the host anti-viral response resulting in increase in viral titers and pro-inflammatory cytokines. Although the higher dexamethasone dose at 10 mg/kg shows a more potent pharmacodynamics effect in mice, 0.5 mg/kg dexamethasone is sufficient to reduce vascular leak.

CONCLUSIONS

This study provides a clear link between timing of dexamethasone treatment and viral burden, vascular leak, and mortality. 0.5 mg/kg dexamethasone affects clinically relevant parameters in the influenza model and has comparable exposure to human dexamethasone dosing; thus it is a more relevant dose to use in future mouse studies.