The role of complement and cytokines as mediators of intracellular sodium accumulation and increased energy demand during critical illness will be studied in collaboration with the other members of the center grant application. The experiments described in this section are based on the hypothesis that complement activation and abnormal cytokine production facilitate and maintain potentially lethal alterations in transmembrane sodium gradients that necessarily affect energy metabolism within the cell. Thus, the role of complement activation, cytokine production, and free radicals in the genesis changes in: 1) sodium and water distribution across the cell membrane; 2) cellular bioenergetics; and 3)intracellular and extracellular pH will be examined. In established rodent models of sepsis, and ischemia and reperfusion injury, the specific aims are to: 1) determine how complement activation and cytokine elaboration affect sodium and water distribution, Na+-K+ ATPase activity, and pH in the gastrocnemius muscle and liver; 2) examine the effect of complement and cytokine inhibition on the transmembrane sodium gradient and secondary changes in high energy phosphate metabolism; and 3) correlate changes in complement activity and cytokine elaboration, as markers of the severity of injury, with changes in phosphocreatine utilization and other in vivo indices of cellular energy state as markers of changes in energy supply and demand within the cell. These relationships will be explored in the gastrocnemius muscle and level of normal rats and in the thigh (vastus lateralis) muscle of normal, complement deficient mice. Changes in sodium and water distribution will be measured using in vivo sodium magnetic resonance spectroscopy (MRS) and the shift reagent triethylenetetraminehexaacetate dysprosium (III) and phosphorus MRS and the MRS-visible water space markers dimethylmethylphosphonate and phenylphosphonate respectively. Phosphocreatine breakdown rates will be measured using in vivo 31P-MRS magnetization transfer techniques. Experimental interventions that will be used to understand the mechanisms of the observed changes will include the administration of endotoxin and TNF and complement blockade using sCR1. These in vivo experiments should clarify the mechanisms by which intracellular sodium content increases during critical illness, improve our understanding of the regulation of cellular bioenergetics and facilitate the development of strategies to ameliorate the effects of sepsis and ischemia-reperfusion injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM052585-06
Application #
6301776
Study Section
Project Start
2000-04-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
6
Fiscal Year
2000
Total Cost
$277,857
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Sadeghipour, Hamed; Torabi, Radbeh; Gottschall, James et al. (2017) Blockade of IgM-Mediated Inflammation Alters Wound Progression in a Swine Model of Partial-Thickness Burn. J Burn Care Res 38:148-160
Sheu, Eric G; Wakatsuki, Kohei; Oakes, Sean et al. (2016) Prevention of intestinal ischemia-reperfusion injury in humanized mice. Surgery 160:436-42
Bankova, L G; Dwyer, D F; Liu, A Y et al. (2015) Maturation of mast cell progenitors to mucosal mast cells during allergic pulmonary inflammation in mice. Mucosal Immunol 8:596-606
Dwyer, Daniel F; Woodruff, Matthew C; Carroll, Michael C et al. (2014) B cells regulate CD4+ T cell responses to papain following B cell receptor-independent papain uptake. J Immunol 193:529-39
Bankova, Lora G; Lezcano, Cecilia; Pejler, Gunnar et al. (2014) Mouse mast cell proteases 4 and 5 mediate epidermal injury through disruption of tight junctions. J Immunol 192:2812-20
Houde, Martin; Jamain, Marc-David; Labonte, Julie et al. (2013) Pivotal role of mouse mast cell protease 4 in the conversion and pressor properties of Big-endothelin-1. J Pharmacol Exp Ther 346:31-7
Gurish, Michael F; Austen, K Frank (2012) Developmental origin and functional specialization of mast cell subsets. Immunity 37:25-33
Younan, George J; Heit, Yvonne I; Dastouri, Pouya et al. (2011) Mast cells are required in the proliferation and remodeling phases of microdeformational wound therapy. Plast Reconstr Surg 128:649e-58e
Afnan, Jalil; Ahmadi-Yazdi, Cyrus; Sheu, Eric G et al. (2010) Inhibition of rat gut reperfusion injury with an agent developed for the mouse. Evidence that amplification of injury by innate immunity is conserved between two animal species. Am J Physiol Regul Integr Comp Physiol 298:R1675-81
Haas, Michael S; Alicot, Elisabeth M; Schuerpf, Franziska et al. (2010) Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction. Cardiovasc Res 87:618-27

Showing the most recent 10 out of 34 publications