Sepsis (systemic inflammatory response to infection) has an incidence of 750,000 cases and is the leading cause of death in critically ill patients. Treatment of sepsis has been limited and remains largely supportive in nature. Improved understanding of the mechanisms underlying inflammation in sepsis and preclinical investigation of interventions designed to reduce mortality are part of the NHLBI mission. Preliminary studies show that the costimulatory molecules, CD80 and CD86 are important in the innate immune response to sepsis. CD80/86-/- mice have improved survival, reduced inflammatory cytokine production and less NF-kappaB activation after polymicrobial sepsis produced by cecal ligation and puncture (CLP). An in vitro model using neutrophil (PMN)/macrophage co-culture leads to macrophage activation by a CD80/86 dependent pathway. During clinical investigation of sepsis we observed that PMN from septic humans have increased expression of a CD28 (a CD80/86 ligand) and mortality correlated with soluble CD28 levels. We hypothesize that macrophage expressed CD80/86 are involved in the innate immune response to sepsis. To determine the specific importance of CD80 and CD86 we will use mice congenitally deficient in these molecules as well as siRNA and inhibitory antibodies to modulate CD80 and CD86 expression in macrophages. We will investigate the expression of the CD80/86 system in human sepsis by flow cytometry and confocal microscopy and compare regulation in humans and mouse to validate the CLP model. We will then assay the effect of PMNs from normal and septic human subjects on macrophages in vitro and assess the role CD80 and CD86 using using siRNA and blocking antibodies in co-culture experiments. This is a proposal for investigation in sepsis and training which includes a completion of a Masters of Science in Clinical Investigation.The course work and the experience in the laboratory under the mentorship of Dr. Weiden are essential for developing my abilities in identifying pathophysiologic mechanisms in model systems. This grant will foster a career focused on understanding the mechanisms underlying inflammation in sepsis with the goal of developing intervensions that reduce mortality in this important disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
3K23HL084191-05S1
Application #
8739733
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Sarkar, Rita
Project Start
2008-05-01
Project End
2014-09-25
Budget Start
2013-09-26
Budget End
2014-09-25
Support Year
5
Fiscal Year
2013
Total Cost
$159,138
Indirect Cost
$11,788
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Lee, Young Im; Smith, Robert L; Gartshteyn, Yevgeniya et al. (2016) Predictors of Acute Hemodynamic Decompensation in Early Sepsis: An Observational Study. J Clin Med Res 8:575-81
Nolan, Anna; Weiden, Michael D (2015) Trends in sepsis and infection sources in the United States. A population-based study. Ann Am Thorac Soc 12:784
Weiden, Michael D; Kwon, Sophia; Caraher, Erin et al. (2015) Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of Distal Airway and Blood Biomarkers that Predict FEV₁ Decline. Semin Respir Crit Care Med 36:323-33
Loupasakis, Konstantinos; Berman, Jessica; Jaber, Nadia et al. (2015) Refractory sarcoid arthritis in World Trade Center-exposed New York City firefighters: a case series. J Clin Rheumatol 21:19-23
Hall, Charles B; Liu, Xiaoxue; Zeig-Owens, Rachel et al. (2015) The Duration of an Exposure Response Gradient between Incident Obstructive Airways Disease and Work at the World Trade Center Site: 2001-2011. PLoS Curr 7:
Cho, Soo Jung; Echevarria, Ghislaine C; Kwon, Sophia et al. (2014) One airway: Biomarkers of protection from upper and lower airway injury after World Trade Center exposure. Respir Med 108:162-70
Schenck, Edward J; Echevarria, Ghislaine C; Girvin, Francis G et al. (2014) Enlarged pulmonary artery is predicted by vascular injury biomarkers and is associated with WTC-Lung Injury in exposed fire fighters: a case-control study. BMJ Open 4:e005575
Niles, Justin K; Webber, Mayris P; Liu, Xiaoxue et al. (2014) The upper respiratory pyramid: early factors and later treatment utilization in World Trade Center exposed firefighters. Am J Ind Med 57:857-65
Tsukiji, Jun; Cho, Soo Jung; Echevarria, Ghislaine C et al. (2014) Lysophosphatidic acid and apolipoprotein A1 predict increased risk of developing World Trade Center-lung injury: a nested case-control study. Biomarkers 19:159-65
Nolan, Anna; Kwon, Sophia; Cho, Soo Jung et al. (2014) MMP-2 and TIMP-1 predict healing of WTC-lung injury in New York City firefighters. Respir Res 15:5

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