Programs and cores

Project 1 : Dynamic Effects of Chemokines on Systemic Inflammation

Project 2: Macrophage Activation /Deactivation in ALI

Project 3: Alveolar Mesenchymal Cells in Acute Lung Injury

Project 4: A Randomized Trial of GM-CSF in Patients with ALI

Core A: Clinical Core

Administrative Core

Project I: Dynamic Effects of Chemokines on Systemic Inflammation;
Steven L. Kunkel, PI

Systemic inflammatory response syndrome (SIRS) is a critical condition developing in patients with severe injury resulting from major surgical insult, trauma, extensive burns, and sepsis. The local and systemic exuberant production of cytokines, at multiple levels, appears to be critical in the progression of this syndrome. Recent evidence suggests that cytokines and chemokines and their receptors participate in the initiation, maintenance, and resolution of this systemic insult. This project focuses on the role of the chemokine receptor CCR4 and its ligand CCL17 (TARC), an interaction that may result in immunoregulation of the host's response and could participate in various aspects of SIRS induced pathology. Preliminary studies suggest that TARC may play an important role in dampening the magnitude of local and systemic inflammation during innate immune responses to microbial challenge. The aims in this project will test the hypothesis that the expression of the chemokine TARC and its receptor CCR4 by structural cells and leukocytes represent key regulatory components of the septic response by modulating early cytokine production, toll-like receptor expression, and leukocyte activation/recruitment. Animal models of abdominal sepsis will be utilized to determine the cellular sources and contributions of CCR4 and it's ligands to sepsis-induced leukocyte activation and tissue injury. These studies will be extended to human disease using BAL fluid and cells obtained from patients with ALI/ARDS. The experimental model systems coupled with an assessment of patient samples will provide a two pronged strategy to determine the balance of specific chemokines and their receptors during the evolution of systemic inflammation, and by doing so may identify novel targets for immune intervention in the treatment of this disease.

PROJECT ABSTRACT

The initation and maintenance of sepsis and acute lung injury are dependent upon a diverse collection of ill-understood cellular and molecular mechanisms, which are likely triggered as a result of an overwhelmed or failed innate immune response and a subsequent cytokine storm. These processes set in motion a cascade of events which significantly contribute to the pathology of this syndrome, including altered physiology, immunosuppression, and impaired healing. Our preliminary data support the concept that during experimental sepsis CCR4 andTARC/CCL17(Thymus and activated-regulated chemokine), possess novel biological activities on both the innate immune response and subsequent down-stream immune systems. Based on these data, we hypothesize that TARC:CCR4 expression, by structural resident cells and leukocytes, respectively, are key regulatory components of the septic response. This mechanistically occurs by modulating early cytokine expression, toll-like receptor (TLR) expression and leukocyte activation and elicitation. The expression of CCR4 and TARC during these initial responses have profound effects on subsequent sepsis pathology. Our studies will focus on the following Specific Aims: 1) to investigate the time-course, magnitude of expression, and cellular sources of CCR4 and TARC during the evolution of experimental sepsis; 2) to determine the mechanistic role by which TARC and CCR4 expression can regulate the progression of experimental sepsis by influencing specific cytokine expression profiles, leukocyte activation and elicitation, and TLR expression; 3) to assess the contribution of resident, structural cell-derived TARC in regulating the innate and subsequent systemic inflammatory response in experimental sepsis; and 4) to investigate the expression of CCR4 and TARC by cells and fluids recovered from patients with clinically defined sepsis and correlate the expression patterns with characterized phases of disease. A number of important tools will be used in this application to determine the cellular and molecular mechanism(s) of TARC:CCR4 induced regulation, including the use of CCR4-/- mice. Both experimental systems of sepsis and clinical specimens will be used to achieve our long term objective, which is to demonstrate the important mechanistic contribution of chemokine receptors and their ligands to the evolving immune response and how these interactions impact on the various phases of sepsis.