Twenty million people abuse alcohol in the United States and 1.8 million alcoholics are hospitalized every year. Alcoholic lung syndrome is recognized as a significant cause of morbidity and mortality amongst this large population, with estimated deaths approaching that of alcohol induced liver cirrhosis. Alcohol abuse induces persistent and profound oxidative stress in the lung, causing an alcohol mediated lung injury defined by dysfunctional epithelial barriers and an exaggerated inflammatory response to acute insults. The alcoholic lung is primed to develop acute respiratory distress syndrome (ARDS), a severe form of pulmonary edema that often precedes respiratory failure. Alcoholics are more susceptible to the insults including pneumonia, trauma, and sepsis, against which the alcoholic lung is predisposed to mount this pathologic hyperinflammatory response. There are no therapies available to treat alcoholic lung syndrome and preserve pulmonary function in this vulnerable population. Recent research suggests that targeting tight junctions in the alcoholic lung is a promising therapeutic approach to preventing loss of epithelial barrier integrity and acute respiratory failure in critically ill alcoholic patients. FirstString Research has developed a novel peptide, termed aCT1, that stabilizes tight junctions, strengthens intercellular barriers, and prevents pathological inflammation. aCT1 is a peptide mimetic of the gap junction protein Connexin43 (Cx43) C-terminus that binds ZO-1, altering interactions with its junctional binding partners. aCT1 peptide stabilizes ZO-1 at the cell membrane, preventing tight junction degradation in response to injury and strengthening epithelial barriers. FirstString Research has currently advanced Granexin® gel, a topical formulation of aCT1 peptide, through three Phase 2 clinical trials for scar reduction and the treatment of chronic wounds. These clinical results have repeatedly demonstrated the ability of aCT1 to stabilize epithelial barriers and promote an effective epithelial response to injury, pathologies core to alcoholic lung syndrome. Preliminary data demonstrate the ability of aCT1 to preserve lung epithelial barrier function and improve survival in response to direct pulmonary insult in vivo. In this Phase I SBIR, we propose to determine the efficacy of aCT1 as a treatment for alcoholic lung syndrome. We believe therapeutically targeting tight junctions in the alcohol damaged lung will stabilize lung epithelial barriers, mitigate the pathological immune response, and prevent development of acute respiratory failure to improve survival of alcoholic patients. Direct targeting of intercellular junctions represents a novel approach to stabilize the air-liquid barrier and preserve lung function in alcoholic lung syndrome. In clinically relevant two-hit models of alcoholic lung syndrome, we will test the ability of aCT1 treatment post insult to preserve epithelial barrier integrity and improve survival in vivo. We will utilize primary airway lung epithelial cells isolated from alcoholic patients to test aCT1 efficacy in restoring barrier function in the human lung, providing further evidence that aCT1 is a viable therapeutic for alcoholic lung syndrome and supporting the further development of this therapy in a Phase II SBIR.
Public Health Relevance Statement: PROJECT NARRATIVE Chronic alcohol consumption causes profound oxidative stress in the lung that injures the pulmonary epithelium and leaves alcoholics predisposed to develop acute respiratory failure. There are no treatments directed at treating alcoholic lung syndrome and improving survival in these patients. The proposed research aims to develop a novel therapy to act as a front line treatment for alcoholic patients and prevent mortality from alcohol mediated lung injury.
Project Terms: Actins; Acute; Acute respiratory failure; Adult Respiratory Distress Syndrome; aerosolized; Air; Alcohol abuse; alcohol exposure; Alcohols; Alveolar; Alveolar Cell; alveolar epithelium; Bacterial Pneumonia; Binding; Cell membrane; Cells; Cessation of life; Chronic; chronic alcohol ingestion; Chronic lung disease; chronic wound; Cicatrix; Clinical; clinically relevant; Connexin 43; Connexins; Critical Illness; cytokine; Cytoskeleton; Data; Development; Endotoxemia; Epithelial; Epithelial Cells; Epithelium; Evaluation; Exposure to; Floods; Formulation; Functional disorder; Gases; Gel; Homeostasis; Hospitalization; Human; immune function; Immune response; Impaired wound healing; Impairment; improved; in vivo; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; innovation; Intercellular Junctions; Liquid substance; Liver Cirrhosis; Lung; Lung diseases; lung injury; lung preservation; Maintenance; Mediating; Membrane; Modeling; Morbidity - disease rate; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; Organ; Oxidative Stress; Pathologic; Pathology; Patients; Peptides; peptidomimetics; Phase; Phase II Clinical Trials; Pneumonia; Population; preservation; prevent; problem drinker; Proteins; Pulmonary Edema; pulmonary function; Rattus; repaired; Research; Respiratory Failure; Respiratory physiology; response; response to injury; restoration; Scaffolding Protein; seal; Secondary to; Sepsis; Site; Small Business Innovation Research Grant; Syndrome; Testing; Therapeutic; therapeutic target; therapy development; Tight Junctions; Time; Tissues; Trauma; United States; Up-Regulation; Vulnerable Populations; zonula occludens-1 protein
