Sepsis continues to be the major complicating factor following injury leading to multiple organ failure and death. Although it is well known that severe accidental injury causes soft and solid tissue destruction resulting in immunodepression, there has not been any systematic investigation addressing the question whether hemorrhage per se, which occurs in conjunction with other accidental injuries as well as a separate pathophysiological entity, play any major role in producing the immunodepression. Moreover, there is no information available concerning the effects of adequate fluid resuscitation following hemorrhage on the immune function. Our hypothesis is that hemorrhage without any significant tissue trauma and even with adequate fluid resuscitation compromises cell-mediated immunity and predisposes to sepsis. Moreover, our hypothesis is that immunomodulation by certain agents (thymopentine, thympoietine, Tuftsin, ATP-MgCl2, interleukin-2 and gamma interferon) following hemorrhage would improve the immune response and decrease the subsequent susceptibility to sepsis. Our plans are to examine the effects of hemorrhage and resuscitation on cell-mediated immunity, lymphokine regulation and natural killer cell activity using a murine hemorrhage model. The mice will be bled to and maintained at different levels of blood pressure for various time periods followed by adequate resuscitation. The time course of immunological alterations will then be measured by studying both the T-cell and macrophage function in vitro. Since Kupffer cell phagocytic activity is known to be depressed after hemorrhage, we will measure both antigen presentation and expression of membrane interleukin-1. These parameters will also be measured in peritoneal macrophages and splenic adherent cells. Antigen presentation by the macrophages is critical for effective activation of T helper cells. Ia antigen expression of Kupffer cells, peritoneal macrophages and splenic adherent cells will also be whether the post-hemorrhage mice are more susceptible to sepsis as produced by cecal ligation and puncture and determine whether the susceptibility to sepsis following hemorrhage can be prevented by immunomodulating agents. Our objective is also to determine whether the stimulatory action of some of the immunostimulating agents is due to influx of Ca2+ into the lymphocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM037127-01A2
Application #
3292185
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Kawasaki, Takashi; Chaudry, Irshad H (2012) The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 1: central nervous system, lung, and heart. J Anesth 26:883-91
Angele, Martin K; Pratschke, Sebastian; Chaudry, Irshad H (2012) Does gender influence outcomes in critically ill patients? Crit Care 16:129
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Kawasaki, Takashi; Suzuki, Takao; Choudhry, Mashkoor A et al. (2010) Salutary effects of 17beta-estradiol on Peyer's patch T cell functions following trauma-hemorrhage. Cytokine 51:166-72
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Jian, Bixi; Wang, Deli; Chen, Dongquan et al. (2010) Hypoxia-induced alteration of mitochondrial genes in cardiomyocytes: role of Bnip3 and Pdk1. Shock 34:169-75
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