Stabilization of Cellular Junctions as a Therapy for Acute Lung Injury
Abstract
On the battlefield, acute lung injury (ALI) can result from exposure to trauma, blast injury, inhalation of noxious substances, exposure to natural or weaponized biologic agents, radioactive substances, or result as a consequence of shock from severe bleeding. ALI is a severe disorder of acute inflammation causing disruption of the cellular integrity in the lung, resulting in leakiness, the influx of edema fluid, and impairment in oxygenation, ultimately resulting in respiratory failure. Patients with ALI require extensive critical care and the long-term debilitating sequelae in survivors include pulmonary, psychological, and neurological impairment. Targeted treatment options include antioxidants and anti-inflammatory medications as well as supportive therapy (i.e., therapeutic agents for the underlying cause, mechanical ventilation, fluid management, nutritional support). However, a lot of these approaches are currently in clinical trials and are not yet approved. Anti-inflammatory agents have shown modest results; however, aggressive anti-inflammatory regimens raise the risk for opportunistic infections. An approved therapeutic to treat ALI does not exist, and despite state-of-the-art intensive care medicine, mortality rates remain high. There is an urgent need to develop new therapeutic compounds that reduce the risk of infectious complications while still providing protection from ALI. This application is in direct response to the Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Area calling for novel therapeutics that reduce the incidence and/or severity of ARDS and/or other lung injury secondary to trauma, transfusion, burns, hemorrhagic shock, and/or oxygen exposure. Protective ventilation strategies are aimed at minimizing lung damage and enabling lung repair and not only do not address the compromised lung integrity underlying the pathology of ALI, but may exacerbate the disease. In addition to resulting in inflammatory cell infiltration, fluid penetration into the lung air space, and the interruption of gas exchange, compromised lung integrity also enables bacteria and viruses to spread from the lung to the bloodstream and onto other organs resulting in systemic infection, and finally organ failure. Therapeutically stabilizing/restoring alveolar-capillary membrane integrity in order to inhibit fluid leakage, neutrophil transmigration, and cytokine production in the alveolar space presents a novel approach to protecting the lungs from the injurious stimuli that lead to lung damage and physiological compromise in ALI. Connexin43 (Cx43) is a critical protein that in expressed in lung cells and has key roles in maintaining the stability and integrity of cellular junctions. The therapeutic application of peptide therapeutics based on sequences of Cx43 have recently shown preclinical and clinical efficacy in safely enhancing wound closure, reducing inflammation, and promoting regeneration of normal tissue at the site of injury or insult via the stabilization of cellular junctions. Our innovative idea is to directly deliver an aerosolized small Cx43-mimetic peptide therapeutic, aCT1, into the lung that is rationally designed to enter pulmonary cells and modulate the interaction of Cx43 with its binding partners. The anticipated result is stabilization of lung integrity, reduction in lung edema, reduction in the ability of infectious agents to enter the lung, and restoration of lung function. Our hypothesis is that aerosolized delivery of aCT1 may have the potential to augment the approach of stabilizing cellular junctions and will therefore be an effective and innovative treatment modality for reducing lung pathology and treating ALI. The completion of the proposed studies will validate the therapeutic potential of stabilizing lung integrity and reducing damaging inflammatory responses using aerosolized delivery of the small Cx43-based peptide therapeutic, aCT1, in clinically relevant sm
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810419
Entities
People
- Gautam Ghatnekar
Organizations
- FirstString Research (United States)
- United States Army