Sepsis is a disease process characterized by a systemic inflammatory response to an underlying infection. In the United States, 750,000 people develop severe sepsis annually and despite recent advances in critical care, over 210,000 people die each year. Polymicrobial sepsis due to intra-abdominal infection accounts for a significant and growing percentage of cases of severe sepsis and is often associated with substantial mortality. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, plays a pivotal role in modulating both the inflammatory and anti-inflammatory innate immune responses and COX-2-derived prostanoids may be vital to gastrointestinal barrier defense during polymicrobial sepsis. Our overall hypothesis is that COX-2 plays a protective role during the host response to intra-abdominal polymicrobial sepsis. Our preliminary data demonstrate that COX-2 deficiency is detrimental in a murine model of peritonitis-induced polymicrobial sepsis. COX-2 deficient mice exhibit exaggerated mortality, severe ileal mucosal damage, increased bacteremia, and enhanced seeding of vital organs following cecal ligation and puncture (CLP).
The Specific Aims of this proposal are: 1) to investigate the role of COX-2-derived prostanoids in a murine model of peritonitis-induced polymicrobial sepsis;2) to elucidate the cell type(s) responsible for mediating the protective effects of COX-2 during peritonitis-induced polymicrobial sepsis;and 3) to determine the mechanisms by which COX-2 affords protection during sepsis. In addition to our scientific goals, the candidate seeks a formal, mentored training program to develop the skills necessary to become a successful physician-scientist. The candidate is an intensivist with a long-standing interest in the pathophysiology of sepsis. Her proposed career development plan includes: 1) mentorship and collaboration with successful leaders in the field of critical care research;2) fundamental training in a wide range of techniques necessary to study clinically relevant models of sepsis;and 3) acquiring the intellectual skills to develop into an independent investigator in academic critical care medicine. SUMMARY: Sepsis is a disease associated with severe infections that afflicts three quarters of a million people each year. There is no specific treatment for sepsis and over 200,000 people die annually of this devastating illness. The main goal of this proposal is to determine how the COX-2 enzyme is protective during sepsis with the hope that this research will eventually lead to new therapies for this frequently fatal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM083207-05
Application #
8197378
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (02))
Program Officer
Somers, Scott D
Project Start
2007-12-11
Project End
2013-05-30
Budget Start
2011-12-01
Budget End
2013-05-30
Support Year
5
Fiscal Year
2012
Total Cost
$120,095
Indirect Cost
$8,896
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Fredenburgh, Laura E; Ma, Jun; Perrella, Mark A (2009) Cyclooxygenase-2 inhibition and hypoxia-induced pulmonary hypertension: effects on pulmonary vascular remodeling and contractility. Trends Cardiovasc Med 19:31-7
Fredenburgh, Laura E; Liang, Olin D; Macias, Alvaro A et al. (2008) Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation 117:2114-22