Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are the most prevalent clinical syndromes associated with severe sepsis and are important causes of morbidity and mortality in United States with a mortality rate of 40%. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, there are several gaps in our knowledge; as a result of which there is currently no effective pharmacologic therapy. In this context, enzymes known as caspases are essential for completion of the apoptotic program. Phagocytes, in particular monocyte/macrophages, are recognized as major components of inflammatory and immunologic reactions in the lung and are rich reservoirs of caspases, especially caspase-1. The function of caspase-1 has recently been recognized to extend beyond the processing and activation of IL-1 and IL-18 to include regulation of NF-kB and induction of apoptosis. The present project seeks to expand upon our recent observation that microparticulate caspase-1 can be released from mononuclear phagocytes to have distant effects on target cells. The present project seeks to investigate a novel hypothesis that links apoptotic enzyme, caspase-1, encapsulated in circulatory vesicles, to lung cell injury and apoptosis. The central hypothesis is that monocyte/macrophage caspase-1 released in target specific microparticles can promote lung cell apoptosis, enhancing lung injury. This project provides a much needed effort and framework to study the poorly understood mechanism of endothelial cell injury and vascular dysfunction in ARDS patients, to enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the cell injury in ALI/ARDS patients. Therefore, to determine the specifics of this novel pathway, we propose the following specific aims: 1) To discover the detailed mechanisms by which monocyte derived extracellular caspase-1 injures lung vascular endothelial cells, 2) To characterize the forms of circulating caspase-1 present in the serum of critically ill patients and 3) To determine how extracellular caspase-1 is taken up by target cells. This project provides an opportunity to examine the role of caspase-1 in the complex biology of monocyte/endothelial cell interactions and apoptosis. Successful completion of this work will uncover critical components of microparticles and caspase-1 mediated inflammasome signaling, enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the lung destruction in septic patients with ALI/ARDS.
Acute lung injury (ALI) and its more severe form, the acute respiratory syndrome (ARDS) is common in patients suffering from conditions such as major trauma, sepsis or shock and is the primary cause of death. The severity of lung injury remains a critical determinant of survival in patients suffering from ARDS and sepsis. A component of this lung injury is due to programmed death of lung cells by poorly understood pathways. This project seeks to identify and characterize a novel cell death pathway caused by a packaged delivery of the enzyme caspase-1 in microparticles. Our study will determine if caspase-1 released in submicroscopic packages may interact with lung cells to induce their death. Studies outlined here will study the formation and release, as well as targeting and cell uptake of these death packages. We expect this approach to uncover novel insights into ARDS mediated lung injury of septic patients and thus create new therapeutic opportunities to prevent and treat patients with ARDS and other inflammatory diseases.
| Mitra, Srabani; Exline, Matthew; Habyarimana, Fabien et al. (2018) Microparticulate Caspase 1 Regulates Gasdermin D and Pulmonary Vascular Endothelial Cell Injury. Am J Respir Cell Mol Biol 59:56-64 |
| Mitra, Srabani; Wewers, Mark D; Sarkar, Anasuya (2015) Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury. PLoS One 10:e0145607 |
| Exline, Matthew C; Justiniano, Steven; Hollyfield, Jennifer L et al. (2014) Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. PLoS One 9:e90968 |
