Exogenous regulation of acute lung injury
Abstract
The lung is the route of first contact with aerosolized and weaponized chemical agents, and consequently exposure often results in respiratory distress. This is the result of various types of fibrin-related inflammation1, including Acute Lung Injury (ALI), Acute Respiratory Disease Syndrome (ARDS), a build-up of bronchial casts, and plastic bronchitis. Early reports indicate that chemical warfare agents (CWAs), specifically choking agents, initiate a system of proinflammatory signals starting with the secretion of cytokines from alveolar macrophages. This is thought to lead to the up-regulation of proinflammatory receptors (PIRs) that then migrate to the cell membrane to perpetuate the response signal. This signaling is involved in fibroblast proliferation and pulmonary fibrosis. A better understanding of the cellular mechanisms resulting from exposure to CWAs would allow us to control the steps in the pathogenic pathway in order to prevent air passage restriction and respiratory distress. Specifically, we start from the perspective that the most advantageous point for regulation would be to block the trafficking of PIRs to the membrane and we propose that fortifying the filamentous (or F-) actin skeleton fence as a barrier to the cell surface could do this. We have recently developed a method for the delivery of proteins to alveolar cells and we have demonstrated that delivering a Rho family GTPase, which up-regulates F-actin, resulted in decreased alveolar expression of PIRs and correlated with significantly increased survival rates in an endotoxin-induced ALI mouse model. With techniques that our laboratory has developed and routinely use, our goal is to determine the cellular response to exposure to CWAs, with a focus on the role of F-actin, and to demonstrate that this response can be externally regulated,thereby preventing the development of fibrin-related inflammation. We have also demonstrated that we can use this system to deliver an enzyme to the lungs in order to clear it of toxin. Thus, this system has a two-fold potential: first to reduce inflammation in response to agent; and second to convert the lung into a decontamination vessel, as a means to protect and defend against chemical agents.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- HDTRA11810049
Entities
People
- Francine Katz
Organizations
- Defense Threat Reduction Agency
- Research Foundation of The City University of New York