Trauma, hemorrhagic shock, and burns initiate cellular immune responses with detrimental effects on the clinical outcome of trauma patients.
In the early phase after trauma, overwhelming inflammation causes neutrophil activation and subsequent organ damage, caused by neutrophil, that can result in adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF).
In the later phase after trauma, suppressive mediators found in the circulation of patients decrease the ability of lymphocytes to protect the trauma victim from invading microorganisms. This can lead to severe infections and sepsis that are major reasons for trauma deaths.
Our group has focused on the cellular and molecular mechanisms that are involved in the cellular immune response to trauma as well as novel therapeutic approaches to modulate this response. Learn more about the different research projects:
- Gamma-Delta T Cells and Resolution of Inflammation
- Neutrophil Activation and Inflammation
- Hyertonic Modulation of the Immune Response
- Purinergic Control of Neutrophil Chemotaxis
- T Cell Activation and Dysfunction
- Purinergic Signaling
ATP release sites (green) of HEK-293 cells colocalize with mitochondria (red). Data obtained with our Leica/Yokogawa CSU-X1/Andor confocal imaging system.
Current Research Projects
Regulation of immune cells by extracellular ATP
Neutrophils and lymphocytes release ATP, which regulates cell responses via autocrine feedback mechanisms that involve ATP, ADP, and adenosine receptors, collectively termed purinergic receptors. Purinergic receptors are found on the surface of all immune cells, allowing them to engage in cell-to-cell communication and to execute complex functional responses such as chemotaxis, which helps neutrophils locate sites of infection. We study these purinergic signaling mechanisms using cell lines as well as immune cells obtained from human and mouse blood samples and confocal life cell imaging techniques, flow cytometry, and a range of biochemical methods.
Age-dependent changes in purinergic immune cell regulation
We found that ATP levels in blood change dramatically with age. In newborns, low ATP levels reduce the function of immune cells because they cannot initiate cell responses. In older individuals, excessively high circulating ATP levels promote inflammatory complications by overstimulating immune cells. We are currently studying how these age-dependent changes in ATP and its breakdown products affect immune cell responses in mouse models of aging. Our goals are to determine the causes of the age-dependent changes in circulating ATP levels and to investigate if modulation of these changes can improve immune function in children and the elderly.
Roles of zinc and other divalent ions in the regulation of cellular immune responses
Many different enzymes regulate extracellular ATP and adenosine levels. All these enzymes require either Ca2+, Mg2+, or Zn2+ to hydrolyze ATP to ADP, AMP, or adenosine. Therefore, the levels of these divalent ions are important for immune cell regulation by ATP and its breakdown products. We are currently studying how changes in the concentrations of these divalent ions influence immune responses in patients with bacterial and viral infections. For this work, we use influenza and bacteria mouse infection models as well as blood samples from healthy human volunteers and from critical care patients. We measure the levels of ATP, its breakdown products, and the concentrations of divalent metal ions with luminometric methods, fluorescence spectrometry, high performance liquid chromatography, time-of-flight mass spectrometry (LC-MS-TOF), and inductively coupled plasma mass spectrometry (ICP-MS).
Regulation of cell metabolism by extracellular ATP and its breakdown products
Our previous work has shown that ATP and its breakdown product adenosine have opposing effects on mitochondrial metabolism in various mammalian cells. Moreover, we found that AMP, an intermediary breakdown product of ATP, results in a rapid shutdown of mitochondrial metabolism in these cells. AMP intraperitoneally injected into mice resulted in a sharp decline in metabolism and body temperature, which was accompanied by a hibernation-like state that lasted for several hours. We are currently studying the underlying cellular mechanisms and the potential clinical use of our findings to protect the brain and other organ tissues following traumatic head injury, cardiac arrest and stroke.
Learn Even More!
Research Gate: Harvard https://www.researchgate.net/profile/Wolfgang-Junger
Research Gate: UCSD https://www.researchgate.net/profile/Wolfgang-Junger-2
Google Scholar https://scholar.google.com/citations?hl=en&user=-Mx4aK4AAAAJ