Our long-term objective is to understand the host factors that regulate the systemic inflammation and pathogenesis of sepsis, which affects 750,000 persons every year in United States alone and causes high mortality worldwide. We recently discovered a novel host factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) that plays a critical role in determining susceptibility to sepsis by regulating a compensatory pathway that controls the induction of protective cellular antioxidants. Nrf2 is a basic leucine zipper transcription factor that regulates the expression of antioxidant genes including the glutathione pathway and heme oxygenase in response to oxidative and inflammatory stress. Global disruption of Nrf2 (Nrf2 -/-) dramatically decreased survival after cecal ligation and puncture (CLP) and endotoxin treatment relative to wild-type mice (Nrf2 +/+). We hypothesize that Nrf2 regulates a host compensatory mechanism that causes transcriptional induction of antioxidant genes, which determines survival during sepsis. Disruption of Nrf2-dependent compensatory antioxidant pathways increases mortality by exaggerating the innate immune response and predisposing lymphocytes to increase apoptosis. This proposal will shed light on the Nrf2-dependent regulation of immunopathogenesis of sepsis and survival after CLP and strives to develop an intervention strategy targeting Nrf2 with a novel small-molecule activator.
Specific Aim 1 : To test the hypothesis that Nrf2 determines survival after CLP by protecting against deregulation of innate immune response by maintaining cellular redox balance.
Specific Aim 2 : To test the hypothesis that Nrf2 improves survival after CLP by attenuating apoptosis of lymphocytes.
Specific Aim 3 : To test the hypothesis of intervening sepsis by increasing Nrf2 activity with a small-molecule activator. The immunopathogenesis of sepsis remains poorly understood. Nrf2 provides a novel link between the regulation of oxidative stress, the innate immune response.and survival during sepsis. These studies may lead to the development of novel strategies based on Nrf2 for intervening in sepsis and improving survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079239-04
Application #
7860279
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2007-08-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$310,707
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kumar, Sarvesh; Reddy L, Chandra Shekhar; Kumar, Yogesh et al. (2012) Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-? induced expression of ICAM-1: structure-activity analysis. Arch Pharm (Weinheim) 345:368-77
Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I et al. (2012) The transcription factor encyclopedia. Genome Biol 13:R24
Kong, Xiaoni; Thimmulappa, Rajesh; Craciun, Florin et al. (2011) Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. Am J Respir Crit Care Med 184:928-38
Gao, Meixia; Singh, Anju; Macri, Kristin et al. (2011) Antioxidant components of naturally-occurring oils exhibit marked anti-inflammatory activity in epithelial cells of the human upper respiratory system. Respir Res 12:92
Reddy, Narsa M; Potteti, Haranatha R; Mariani, Thomas J et al. (2011) Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol 45:1161-8
Kong, Xiaoni; Thimmulappa, Rajesh; Kombairaju, Ponvijay et al. (2010) NADPH oxidase-dependent reactive oxygen species mediate amplified TLR4 signaling and sepsis-induced mortality in Nrf2-deficient mice. J Immunol 185:569-77
Harvey, C J; Thimmulappa, R K; Singh, A et al. (2009) Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic Biol Med 46:443-53
Taylor, Ronald C; Acquaah-Mensah, George; Singhal, Mudita et al. (2008) Network inference algorithms elucidate Nrf2 regulation of mouse lung oxidative stress. PLoS Comput Biol 4:e1000166
Biswal, Shyam; Remick, Daniel G (2007) Sepsis: redox mechanisms and therapeutic opportunities. Antioxid Redox Signal 9:1959-61
Thimmulappa, Rajesh K; Fuchs, Ralph J; Malhotra, Deepti et al. (2007) Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 9:1963-70