A novel therapeutic strategy for Acute Lung Injury: Inhibition of PKC-delta

DESCRIPTION (provided by applicant): Sepsis and the related systemic inflammatory response are the leading causes of death in intensive care units. More than 200,000 people die each year in the US from sepsis and associated complications. The lung is the organ most often affected with pulmonary dysfunction resulting in acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS). Mortality in patients with ALI/ARDS ranges from 30-60% and recovery often is associated with long term pulmonary and non-pulmonary morbidity. ALI/ARDS is characterized by an intense systemic inflammatory response leading to neutrophil infiltration of the lungs and lung tissue damage. Neutrophil dysfunction plays an important role in the early course of lunginjury through the release of proteases and oxygen radicals that damage pulmonary tissue. Treatment of ALI/ARDS is primarily supportive and there is an urgent need for the development of novel therapeutic approaches directed at the underlying pathophysiology. As the inflammatory response in sepsis is complex and comprised of multiple redundant and overlapping signaling pathways, rather than to focus on a single pathway, we chose to identify specific control points regulating multiple pathways. We identified Protein Kinase C-delta (PKC ) as a critical regulator of the inflammatory response. PKC is activated during sepsis in response to inflammatory mediators including LPS, TNF and IL-1. In PKC null mice, neutrophil activation and migration are limited in response to pulmonary inflammation. Recently, we demonstrated that pulmonary inhibition of PKC had a dramatic anti-inflammatory and lung protective effect in a rodent model of sepsis-induced ALI/ARDS indicating targeting PKC may offer a novel treatment option for ALI/ARDS. Therapeutically relevant inhibition of PKC has been problematic due to the lack of selectivity of currently available small molecule antagonists. CompleGen has identified a new PKC selective inhibitor (CGX1037), using our proprietary XenoGene technology. To test this novel strategy, we will use a well-characterized clinically-relevant rat model of ALI/ARDS (polymicrobial sepsis). The objectives of this project are to: 1) Evaluate the efficacy of the PKC inhibitor, CGX1037, as a therapeutic for the treatment of sepsis-induced lung injury, and 2) determine the pharmacokinetic and pharmacodynamic properties of CGX1037. The long-term goal of this Phase I STTR proposal is to develop a new class of therapeutics for the treatment of lung injury where no specific therapy is currently available. This approach could significantly decrease the morbidity and mortality associated with sepsis. PUBLIC HEALTH RELEVANCE: The development of Acute Lung Injury (ALI) and the more severe Acute Respiratory Distress Syndrome (ARDS) is a major public health problem world-wide and one of the leading causes of death in intensive care units. Current treatment is largely supportive and no pharmacologic therapies are available. The proposed studies will determine whether control of a specific protein kinase C, delta-PKC, in an animal model of ALI/ARDS will prevent lung injury and offer a unique therapeutic target for the treatment of ALI/ARDS.