Department of Anesthesiology/Critical Care Medicine
The Johns Hopkins University School of Medicine
600 North Wolfe Street, Meyer 297 A
Baltimore, MD 21287
Dr. Ralph Fuchs' overarching goal is to translate his research findings to improve the survival rates of patients with septic shock, and he conducts his investigations from two perspectives.
In the first, he seeks to define the role of disrupted iron homeostasis in altering immunity and survival in sepsis. To accomplish that, he and his colleagues are working to validate an iron-overloaded murine model system to determine the role of in vivo iron in bacterial infection and sepsis. In their sepsis model, the investigators monitor survival while measuring iron overload and immune-specific markers.
The second aspect of Dr. Fuchs' research translates directly to patient care. He seeks to define the role of the transcription factor Nrf-2 (which was only recently identified) in regulating immunity, inflammation, and redox balance (the balance between oxidants and antioxidants) under conditions of septic shock in critically ill adults. Nrf-2 is a factor that regulates all antioxidants in experimental sepsis, as it upregulates a network of cytoprotective mechanisms, including genes that regulate cellular iron homeostasis. It has been shown to play a critical role in determining susceptibility to experimental sepsis and septic shock. Dr. Fuchs and his colleagues have already completed a preclinical evaluation in healthy volunteers that showed that triterpenoid analogs, which act as Nrf-2 activators, blocked the oxidative stress and inflammatory responses elicited by endotoxin in human peripheral blood mononuclear cells (PBMCs) and neutrophils (Thimmulappa RK et al. Antioxid Redox Signal 9(11):1963–70, 2007). The group now hypothesizes that diminished Nrf2 activity in patients with septic shock is associated with increased morbidity and mortality secondary to a disruption in the normal immune response to infection and that increasing Nrf2 activity in PBMCs and neutrophils of patients with septic shock would protect against deregulation of the innate immune response by maintaining the redox balance.
As Principal Investigator, Dr. Fuchs is leading the interdisciplinary team that is conducting a prospective cohort study in which they are isolating PBMCs and neutrophils from adult patients in the intensive care unit who are in septic shock; they plan to measure Nrf2 activity to determine its impact on mortality, length of stay, vasopressor days, and ventilator days. In addition, they intend to evaluate the potency of an Nrf2 activator to express more Nrf2 activity ex vivo using PBMCs and neutrophils of patients with septic shock.
- American Society of Anesthesiologists
- American Society of Critical Care Anesthesiologists
- Society of Critical Care Medicine
- International Anesthesia Research Society
- Maryland Society of Anesthesiologists
- American Medical Association
- Fuchs RJ, Lee WA, Seubert C, Gelman S. Transient paraplegia after stent grafting of a descending thoracic aortic aneurysm treated with cerebrospinal fluid drainage. J Clin Anesth 15(1):59–63, 2003.
- Xu X, Pin S, Gathinji M, Fuchs R, Harris ZL. Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis. Ann N Y Acad Sci 1012:1–7, 2004.
- Fuchs RJ, Berenholtz S, Dorman T. How do intensivists improve outcome? Contemp Crit Care 1(12), 2004.
- Fuchs R, Levin J, Tadel M, Merritt W: Perioperative coagulation management in a patient with afibrinogenemia undergoing liver transplantation. Liver Transpl 13(5):752–6, 2007.
- Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Trarore K, Bream JH, Trush MA, Liby KT, Spoorn M, Kensler TW, Biswal S. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Imand CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 9(11):1963–70, 2007.
Laboratory Members/Key Associates
Peter Pronovost, MD, PhD
Brian London, BS, BA
Collaborators—JHU School of Public Health
Shyam Biswal, PhD
Rajesh Thimmulappa, PhD
Ana Navas-Acien, MD, MPH
Sanjeev Noel, PhD
- Clinical Scholar Research Award, International Anesthesia Research Society (2008)
- Medical Dissertation/Doctoral Thesis, Magna Cum Laude (2001)