The central goal of this work is to develop intravenously (IV)-injected Poly-Aspirin (Poly-A) particles as passive restraints of neutrophil function for therapeutic intervention in Acute Lung Injury (ALI). ALI is a rapidly progressing inflammatory disease characterized by the disruption of the lung endothelial and epithelial barriers, leading to accumulation of fluids in the lung airway and hence impaired lung function. ALI together with acute respiratory distress syndrome (ARDS), a more severe form of ALI, affects ~200,000 patients per year in the US currently, with a mortality rate of ~40-60%. To date, there is no one pharmacological strategy effective towards reducing the mortality in ALI/ARDS, likely due to the numerous and complex set of pathological events that can lead to this disease. Thus, the primary treatment for this disease is the use of a mechanical ventilator for blood oxygenation and CO2 removal to allow the damaged lung to heal, but this can lead to further damage to the lung if not employed with care. Neutrophils have been identified as the primary perpetrator of inflammation in ALI/ARDS, where their excessive migration into the lungs contributes to the destruction of the alveolar-capillary barrier that leads to edema in the lungs. Indeed, disease severity correlates with the concentration of neutrophils in the lung airways. Thus, halting the destructive potential of unwanted neutrophil accumulation has been a principal focus for the development of ALI/ARDS treatment. However, prior attempts at developing drugs that block neutrophil signaling/adhesion molecules have met with limited success due to the numerous redundancies in the inflammatory response cascade. Here, we propose to rationally design vascular-targeted particles (VTPs) that physically interact with neutrophils to passively and rapidly block neutrophil accumulation into inflamed tissue in ALI/ARDS. Our main hypothesis is that VTPs interact with neutrophils in the bloodstream, via physical interaction and competition for vascular binding space, to alter neutrophil adhesion to the vessel wall, which critically impacts their migration into the diseased tissue. In this proposal, we harness these blocking interactions to develop a biodegradable, biocompatible VTPs as an effective treatment for ALI/ARDS through three Aims. First, we will fabricate a PolyAspirin-based VTP system and evaluate the impact of their particle size and surface characteristics on their ability to specifically block neutrophil adhesion to the vessel wall in vitro. Second, we will visualize, via intravital microscopy imaging, the adhesion of the PolyAspirin-based VTPs to the blood vessel wall and their blocking of neutrophil adhesion in vivo in inflamed mesentery tissue in mice. Thirdly, we will evaluate the therapeutic functionality of PolyAspirin particles in mice with bacteria-induced ALI/ARDS, representing a realistic model of the human disease. Overall, the knowledge gained from these Aims is expected to drive the future development of novel particle-based anti-inflammatory therapeutics in the treatment of ALI/ARDS. The proposed direct action of VTPs on neutrophils, rather than blocking of adhesion or signaling molecules, will ensure that the proposed system can function irrespective of the primary cause of ALI/ARDS.
The central goal of this work is to develop intravenously (IV)-injected Poly-Aspirin (Poly-A) particles as passive restraints of neutrophil function for therapeutic intervention in Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The demonstrated direct action of particles on neutrophils, rather than the blocking of signaling molecules, will ensure that the proposed system can function irrespective of the primary cause of ALI, which would help reduce the high mortality rate (~40-50%) associated with this disease. The natural anti-inflammatory characteristic of the Poly-A polymer would allow for dry storage of the proposed particle system such that it can be administrated in any clinical setting.
