Sepsis and the related systemic inflammatory response is a major public health problem and one of 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). ALI/ARDS is characterized by an intense inflammatory response leading to neutrophil infiltration of the lungs and lung tissue damage. Neutrophil dysfunction plays an important role in the early course of lung injury 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. To date, there are no specific pharmacologic therapies available that protect the lung from neutrophil-mediated damage. We identified Protein Kinase C-delta (?-PKC) as a critical regulator of the inflammatory response. ?-PKC regulates recruitment and activation of neutrophils in the lungs, and is, therefore, an important target for control of neutrophil-mediated lung damage in ALI/ARDS. ?-PKC is activated by multiple proinflammatory stimuli including the cytokines TNF and IL-1 as well as pathogen associated molecular patterns such as LPS. We hypothesize that sepsis and the associated systemic inflammatory response activates ?-PKC and this kinase plays an important role in the initiation and perpetuation of inflammation and the development of tissue damage in sepsis-associated lung injury. We propose that selective inhibition of ?-PKC offers a unique therapeutic intervention that would target multiple sites in th inflammatory response and prevent neutrophil-mediated lung injury and the development of ALI/ARDS. ?-PKC can be selectively inhibited by a peptide antagonist which through linkage to a TAT peptide is taken up intracellularly to inhibit ?-PKC activity. In a rat model of ALI/ARDS, intra-tracheal delivery of this ?-PKC TAT peptide inhibitor directly into the lungs had a dramatic anti-inflammatory and lung protective effect. To build upon these proofs-of- concept studies, we will use a well-characterized clinically-relevant rat model of ALI/ARDS (polymicrobial sepsis). To test this novel strategy: We will: 1. Determine the biodistribution and in vivo efficacy of intra- tracheal administration of the ?-PKC TAT inhibitory peptide in the lung. 2. Define the mechanistic role of ?-PKC in regulating the inflammatory response in the lung. 3. Evaluate the role of ?-PKC In sepsis- associated lung injury. 4. Test the hypothesis that targeted inhibition of ?-PKC is protective and improves survival in our animal model of ARDS. The proposed studies will provide important insight into the underlying pathophysiology of ALI/ARDS and further define the efficacy of targeted ?-PKC inhibition as a novel therapeutic target in the treatment of ALI/ARDS.
The development of 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 the lungs of an animal model of ARDS will prevent lung injury and offer a unique therapeutic target for the treatment of ARDS.
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