Dr. Metz’s research focuses on inflammation, a complex biological response to infection and injury, in both pregnant and non-pregnant populations. Under healthy conditions, inflammation protects the body and promotes healing. However, when inflammation is excessive or prolonged (e.g. severe infections, arthritis, and ischemic injury caused by decreased blood flow), it damages the body. Her work identifying ways to reduce and prevent dysfunctional inflammation has been funded by the American Heart Association, the National Institutes of Health and the NY State Dept of Public Health. Dr. Metz has published over 110 peer-reviewed research papers and book chapters, and has been an inventor or co-inventor on five patents.
The Laboratory of Medicinal Biochemistry focuses on the regulation of inflammation (defined as the body’s response to infection or tissue injury). Some of the research investigates inflammation during pregnancy (maternal and fetal inflammatory responses) and the other research is unrelated to pregnancy. The inflammatory response is absolutely critical for the body to protect itself following infection or tissue injury, but when inflammation is excessive or sustained it can lead to serious tissue and/or organ damage. Much of the team’s work centers on endothelial cells which line the body’s blood vessels to create ‘slippery tubes’ that facilitate the rapid transport of blood and immune cells throughout the body, particularly to sites of infection and inflammation. Uncontrolled endothelial cell activation, endothelial cell permeability, and immune cell infiltration are characteristic features of many diseases/conditions associated with dysregulated inflammation (e.g. severe infections, arthritis, and ischemic injury caused by decreased blood flow). Therefore, the endothelium is a critical target for anti-inflammation strategies (Tracey and Metz, The Comprehensive Treatise on the Endothelium, 2007).
Regulation of Inflammation Using Nicotinic Acetylcholine Receptor Agonists
Sepsis, a leading complication of surgery and trauma, is a condition characterized by an uncontrolled systemic inflammatory response (with excessive inflammatory mediator production and endothelial cell activation) associated with infection. Despite numerous advances for the treatment of sepsis, the mortality rate for septic patients is between 20-50%. Using experimental models of inflammation, the lab discovered that cholinergic stimulation (using nicotinic acetylcholine receptor (nAChR) agonists or drugs, e.g. nicotine and GTS-21) suppresses excessive endothelial cell activation and inflammatory mediator production in vitro and in vivo and reduce immune cell trafficking during acute inflammation (Saeed et al, JEM 2005). Further studies showed that treatment with nAChR agonists protect against acute kidney injury associated with sepsis/endotoxemia (Chatterjee et al, PLoS ONE 2011). Septic patients who develop acute kidney injury are at increased risk of death and unfortunately, there are no ways to prevent sepsis-associated kidney injury and no effective treatments for kidney injury during sepsis. These studies are important because they support developing a novel treatment for sepsis patients. Similarly, nAChR agonists protect the kidneys from damage following ischemia reperfusion injury (Yeboah et al, Kidney Int’l 2008; Yeboah et al, Am J Physiol Renal Physiol 2008). Kidney ischemia reperfusion injury is a leading cause of acute renal failure. Acute renal failure is common in patients after trauma, hemorrhagic shock, cardiopulmonary bypass surgery, and sepsis. Like septic-acute kidney injury, there are no therapeutic agents for preventing or treating acute renal damage following ischemia reperfusion injury. The advantage of nAChR agonists is that they target multiple targets and pathways simultaneously.
Precisely how the nAChR agonists reduce excessive inflammation and guard against tissue/organ injury is not completely understood. Using various model systems, including human endothelial cell cultures and experimental models, they have identified several pathways targeted by nAChR agonists to control endothelial cell activation, cytokine production, and immune cell trafficking, including the NFkB (Saeed et al, JEM 2005) and JAK2/STAT3 pathways (Chatterjee et al, Am J Physiol Cell Phyiol 2009). In collaboration with an investigator at the Feinstein Institutes, they discovered that the control of NFkB activation by nAChR agonists is mediated, in part, through the regulation of the ubiquitin-proteasome system (Chatterjee et al, PLoS ONE 2011). The ubiquitin-proteasome system is the major non-lysosomal mechanism responsible for degrading regulatory cellular proteins such as IkBa, the inhibitory subunit of NFkB, as well as misfolded, damaged, and/or unnecessary proteins. Based on their ability to regulate NFkB-mediated inflammation, proteasome inhibitors have emerged as potential treatments for numerous inflammatory conditions. In ongoing studies, they are examining how nAChR agonists regulate proteasome activity and how they could be further developed as potential therapies for inhibiting excessive or sustained inflammation.
Maternal Fetal Medicine Research Program: Investigating the maternal and fetal/neonatal consequences of inflammation during pregnancy
The Metz laboratory collaborates closely with clinicians and fellows from the Division of Maternal Fetal Medicine (MFM) in the Department of Obstetrics and Gynecology of the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. In collaboration with Dr. Burton Rochelson, MD, the lab discovered that magnesium sulfate, a tocolytic agent used to delay pre-term labor, suppressed the activation of human umbilical vein endothelial cells through NFkB signaling (Rochelson et al., J Repro Immunol 2007). These observations support recent studies revealing that maternal administration of magnesium sulfate during preterm labor reduces the risk of cerebral palsy in the children. Cerebral palsy is characterized by brain damage which affects motor and cognitive functions and there is evidence that intrauterine infections, fetal inflammatory responses, and perinatal brain lesions increase the risk of cerebral palsy. Consistent with the fetal neuroprotective effect of magnesium sulfate in humans, using experimental model systems we recently found that maternal magnesium sulfate administration reduced both maternal and fetal inflammation (including the fetal brain and placenta) (Tam Tam et al, AJOG 2011; Dowling et al, Placenta 2012). Mechanistic studies support our previous work demonstrating the regulation of NFkB activation by magnesium sulfate (Tam Tam et al, AJOG 2011; Dowling et al, Placenta 2012). Using experimental models of maternal infection and intrauterine growth restriction, the lab continues to investigate the regulation of maternal and fetal inflammation and how inflammation during pregnancy correlates with various maternal and fetal/neonatal outcomes.
More recent studies conducted by the Metz lab focus on exposures and responses during pregnancy that may affect not only maternal, fetal, and neonatal outcomes, but also may result in long-lasting effects on the offspring’s growth, metabolism, and disease susceptibility into adulthood. This exciting area of research investigating how a suboptimal maternal-fetal environment negatively impacts the offspring into adulthood is known as fetal programming. The lab’s preliminary data provide clear evidence supporting the impact of early interventions (during pregnancy) to improve the long-term health of the offspring.
Dr. Metz’s lab-based studies centered on better understanding conditions that negatively impact the health of pregnant mothers and their babies (e.g. preterm labor, preeclampsia, maternal infections, intrauterine growth restriction, obesity, and gestational diabetes) are complemented by resources provided through the Generations Project. The Generations Project is one of the largest longitudinal studies of pregnant women and their offspring in a single institution (PI: PK Gregersen, MD; Co-Investigator: C Metz). It is a collaboration between the Steven and Alexandra Cohen Children’s Medical Center of New York, Long Island Jewish Medical Center, North Shore University Hospital, and the Feinstein Institutes for Medical Research. The program is expected to enroll at least 10,000 pregnant women and follow the mothers/children for 18 years. The purpose of the Generations Project is to establish a resource of clinical, genetics, proteomics/gene expression and microbiome data and biological materials to support research projects investigating environmental, genetic and epigenetic factors associated with a range of complex conditions/diseases including, maternal-fetal health, as well as autism, asthma, childhood obesity, precocious puberty, diabetes, and cancer.