Trauma causes over 140,000 deaths per year in the USA. Most patients with survivable injuries who die, die from multi-system organ failure and the adult respiratory distress syndrome ARDS. ARDS is in great measure a function of PMN attack on the lung as a manifestation of the Systemic Inflammatory Response Syndrome (SIRS). Although many mediators participate in priming PMN attack on the lung, the C-X-C chemokine (CXC) IL-8 primes PMN and has a clear statistical association with ARDS. It has been shown that IL-8 enters the circulation from injury sites, and modulates PMN activity via cytoplasmic calcium ([Ca 2+]i ) fluxes. Calcium fluxes are central cell signaling mechanisms by which PMN can integrate many extracellular stimuli, and moreover high [Ca2+]i fluxes commit PMN to activities such as respiratory burst and degranulation. Preliminary studies showed [Ca2+]i responses of human PMN to physiologic IL-8 doses were increased into a range where 02-burst activity may be expected (251 v 218 nM, p=.03) after incubation in plasma from patients with ARDS. Also, a complex cross-regulation of PMN [Ca 2+]i responses to CXCs have been described which result from interactions of the two CXC receptors (RI and R2) such that GRO-alpha at CXCR2 primes IL-8 responses (242 v 201 nM, p=.003) but IL-8 totally inhibits response to GRO-alpha. This normal regulation is disturbed in PMN from trauma patients. The investigators therefore propose to investigate the hypothesis that clinically significant PMN hyperactivity after major trauma may be mediated by abnormal PMN [Ca2+]i responses to CXCs. Such investigations are likely to benefit trauma patients by suggesting specific approaches to clinical management as well as novel molecular approaches to the modification of PMN-pulmonary interactions in trauma. This application proposes to determine the role of PMN specific CXCs such as IL-8 and GRO-alpha in the mediation of trauma-induced PMN hyperactivity, and in the subsequent development of ARDS. Additionally, it proposes to describe the mechanisms by which the in-vivo circulatory milieu modulates human PMN responses to CXCs, as well as the cellular mechanisms by which CXCs prime PMN activity and potentiate PMN attack on the human lung after injury.
AIM 1 : To identify changes in [Ca2+]i responses of PMNs to CXCs after injury which contribute to the creation of a hyper responsive state and predispose to post-traumatic ARDs, and then to correlate those changes with demographics, clinical measures of injury severity, and patient outcome with respect to ARDS.
AIM 2 : To identify the specific humoral, cellular and molecular mechanisms whereby PMN [Ca2+]i responses to CXCs are disturbed in the setting of trauma and predispose trauma patients to ARDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059179-03
Application #
6519986
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2000-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$274,750
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
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