Exogenous Surfactant as a Pulmonary Drug Delivery Vehicle for Budesonide in the Treatment of ARDS
Authors: Baer Brandon , McCaig Lynda , Sivasri Thebika , Sun Eric , Yamashita Cory , Veldhuizen Ruud 
Published: April 2020

Background

Inflammation associated with diseases like Acute Respiratory Distress Syndrome (ARDS) and Bacterial Pneumonia, often occurs in the deeper, alveolar, areas of the lung. In these circumstances the complex branching structure of the lung, its large surface area, and associated areas of airway collapse provide substantial hurdles for adequate delivery of anti‐inflammatory drugs to remote regions of inflammation. To address this, our lab has utilized a bovine derived exogenous surfactant (BLES) as a pulmonary vehicle to facilitate the transport of a glucocorticoid (budesonide). Budesonide is a strong anti‐inflammatory drug currently used in the lung to treat asthma, while BLES can open collapsed airways and spread to distal sites within the lung.

Hypothesis

Combining budesonide with a bovine derived exogenous surfactant will enhance its delivery and efficacy for treating pulmonary inflammation.

Methods

Our hypothesis was tested using both in vitro and in vivo methodology. For in vitro studies the wet bridge transfer system was utilized to assess spreading and efficacy of budesonide alone or in combination with BLES across an air‐liquid interface. In this system, macrophages were seeded to a remote site and stimulated with heat‐killed bacteria (HKB). Treatments were then administered to a delivery site and IL‐6 concentrations were measured at the remote site. An in vivo model of pulmonary inflammation was created by instilling either saline (control) or HKB into the lungs of male and female rats. This first instillation was followed 30 minutes later by a second instillation of either saline, budesonide or BLES/budesonide. Rats were then monitored for six hours before being euthanized. A bronchoalveolar lavage (BAL) was performed, followed by cell counts and differentials.

Results

The in vitro data showed that administering BLES or budesonide alone had no effect on IL‐6 concentrations at the remote site, across the air‐liquid interface. However, the administration of BLES/budesonide significantly reduced IL‐6 content at the remote site. Data collected from the in vivo experiment indicates that instillation of HKB significantly increased the number of inflammatory cells and neutrophils in the BAL compared to the control. Budesonide alone was able to show a reduction in the number of neutrophils in the BAL. However, BLES/budesonide showed significant reductions in both the number of inflammatory cells and neutrophils in the BAL compared to budesonide and HKB groups.

Discussion

The in vitro data indicates that BLES/budesonide is more effective at reaching and eliciting an anti‐inflammatory effect at a distal site than budesonide alone. Moreover, administering budesonide with BLES in vivo resulted in significant improvements in drug delivery and efficacy. Further measurements of pulmonary inflammation will include myeloperoxidase assays as well as quantifying pro‐inflammatory cytokine mRNA and protein through qPCR and ELISA assays respectively. This novel strategy of utilizing a spreading agent to delivery budesonide represents a new therapy for pulmonary inflammation and a novel approach for directly delivering drugs to distal regions in the lung of ARDS patients.

Support or Funding Information

Ontario Graduate Scholarship ‐ Doctoral