Severe infections, various types of trauma, and other etiologic factors can cause ALI that rapidly morphs into ARDS. The incidence of ALI/ARDS is around 190,000 in adults in US alone. Despite medical advances and better management through ventilation-intervention, the mortality is still unacceptably high at 32-45%. This problem is likely to escalate given the aging population and can be a severe drain on our healthcare budget. There is no formally recommended drug therapy in place for ALI patients except for switching to low volume ventilators. Thus, there is a pressing need for highly effective therapies for ALI/ARDS. In ALI/ARDS, the initial exudative phase is characterized by damage to the pulmonary endothelium and alveolar epithelium that results in leakage of protein rich fluid into the interstitium and alveoli, along with inflammatory cells and RBCs. At the onset of this phase, neutrophils adhere to the activated endothelium, and navigate into lung tissue, thereby triggering a surge of inflammatory cytokines that cause the damage. We propose to combat ALI/ARDS by using nanotechnology; specifically, we will use a proof-of-principle drug piceatannol, a naturally occurring plant stilbene, chemically conjugated to albumin nanoparticles (PANPs) to dis-adhere neutrophils tightly adherent to the activated lung vascular endothelium. Piceatannol is a metabolite of resveratrol, with significant anti-inflammatory properties. In supporting studies, to overcome the solubility issue, we conjugated piceatannol to albumin nanoparticles (PANPs). We observed that PANPs targeted adherent neutrophils and that these neutrophils achieved high effective intra-cellular concentrations of the drug. Using this innovative approach, we demonstrated that PANP prevented ALI induced by i.v. challenge of TNF? and LPS in mice. We will therefore under the auspices of this STTR exploit the novel PANP strategy to reverse the course of ALI and thereby prevent ARDS. In Phase 1, we will have two following specific aims to develop systematically the therapeutic potential of this novel nanotechnology.
Specific Aim 1 : Determine the efficacy of i.v. administered PANPs in reversing the progression of endotoxin-, CLP- and P. aeruginosa in robust ALI/ARDS mouse models causing severe ALI, and determine whether the treatment is efficacious without compromising the lung's intrinsic host-defense function.
Specific Aim 2 : Determine role of PANPs in dis-adhering the adherent neutrophils from activated endothelial cells as a primary mechanism of restoring lung homeostasis and rule out the possibility that the detached neutrophils are injuring distal organs such as the liver.
ALI/ARDS is a disease with high mortality rate (35-40%) with significant disparities in the elderly and African-descent and Latino patients who are particularly susceptible. ALI/ARDS patients also require extensive stays in ICUs and typically receive mechanical ventilation to overcome severe hypoxia and respiratory failure. Unfortunately, mechanical ventilation itself can exacerbate the lung injury. There are no standard pharmacological treatments effective for ALI. We propose to determine the efficacy of piceatannol loaded albumin nanoparticles in 3 ALI/ARDS mouse models based on our preliminary data showing the potential effectiveness of this nanotechnology approach. As described below, our nanodrug suppresses the initial steps in inflammation that precedes ALI by 'de-adhering' the neutrophils binding to the activated vascular endothelium, thereby preventing the development of uncontrolled lung inflammation, the root cause of compromised lungs, vascular leakiness and edema in lungs.
