Mice are one of the most commonly utilized species for the initial study of many infectious diseases, including the study of the host response to bacteria. However, mice are 100 to 100,000- fold more resistant than humans in most biological responses to the effects of bacterial lipopolysaccharide (LPS), and to many other microbial toxins. In the literature, and in our hands, macrophages from the two species are generally similar in their sensitivity to LPS, regardless of source. Our preliminary data indicate that there is a soluble substance in the serum of mice that strongly suppresses the production of IL-6 and TNF from mouse and human macrophages that are stimulated with many pathogen associated molecular pattern molecules (PAMPs). These data raise the possibility that the reason that mice are resistant to LPS and other bacterial toxins is the presence of this factor in their blood. The overall goal of the proposed work is to understand the mechanism(s) by which mice are resistant to LPS. Our first specific aim is to systematically study the sensitivity of macrophages and endothelial cells from different tissue compartments from mice and humans (where possible), as well as in cell lines, in the presence of serum from LPS-resistant animals (eg rodent, baboon) and LPS-sensitive animals (eg human, fetal calf). Our second specific aim is to purify the material from mouse serum that inhibits the production of TNF from mouse macrophages. Our third specific aim is to study the cellular level of signaling that is inhibited. The project has broad significance because most experiments using mouse cells are currently performed using media supplemented with fetal calf serum rather than mouse serum, because the proposed work will further our understanding of sepsis caused by bacterial pathogens, and because the work could eventually lead to better animal models for the study of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059010-04
Application #
7371022
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Sawyer, Richard T
Project Start
2005-06-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$382,369
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Lin, Tian; Liu, Jialin; Huang, Feng et al. (2016) Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis. Mol Med 22:22-31
Lin, Tian; Maita, Dayana; Thundivalappil, Sujatha R et al. (2015) Hemopexin in severe inflammation and infection: mouse models and human diseases. Crit Care 19:166
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Lin, Tian; Sammy, Fatima; Yang, Huan et al. (2012) Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation. J Immunol 189:2017-22
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Lin, Tian; Kwak, Young Ho; Sammy, Fatima et al. (2010) Synergistic inflammation is induced by blood degradation products with microbial Toll-like receptor agonists and is blocked by hemopexin. J Infect Dis 202:624-32
Liang, Xueya; Lin, Tian; Sun, Guangjie et al. (2009) Hemopexin down-regulates LPS-induced proinflammatory cytokines from macrophages. J Leukoc Biol 86:229-35
Warren, H Shaw (2009) Peroxisome proliferator-activated receptor-gamma agonists, control of bacterial outgrowth, and inflammation. Crit Care Med 37:773-4
Warren, H Shaw (2009) Editorial: Mouse models to study sepsis syndrome in humans. J Leukoc Biol 86:199-201

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