Post-resuscitation Injury - Translational Approaches to Cell Signaling in Shock and Resuscitation

Neutrophil Calcium Signaling in Shock and Trauma

Carl J. Hauser, MD, FACS, FCCM, Visiting Professor of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, cjhauser@caregroup.harvard.edu

Each year in the United States, trauma kills 150,000 people, mostly young adults. One third of these deaths occur in the hospital as a result of organ failure or sepsis. Both organ failure and sepsis are closely linked to the body’s immune system. If trauma causes the immune system to become over-activated, excessive inflammation can fatally damage organs, but if the immune system is slow to fire up, the body can be overwhelmed by infection. Understanding the cellular signaling pathways involved in the immune response to shock may help doctors prevent trauma victims from succumbing to organ failure and sepsis.

Calcium plays a major signaling role in many cells in the body, and cells maintain large (50,000-fold) calcium gradients across their plasma membranes. Although neutrophils are classified as non-excitable cells because their membrane calcium channels are not voltage-gated, calcium signals are very important to neutrophil functions ranging from chemotaxis to apoptosis.

Calcium signaling involves many pathways. In one, G-protein coupled receptors on the cell surface activate a cascade of messengers that leads to the release of calcium stored in the endoplasmic reticulum. This calcium release, in turn, triggers surface channels to allow external calcium to enter the cell. In many types of cells, calcium-entry disorders cause disease, including severe combined immunodeficiency.

Many membrane lipid derivatives, such as sphingosine-1-phosphate, promote external calcium entry, and all these lipid messengers are suppressed by trauma. These messengers seem to work by altering lipid raft composition, which affects membrane curvature and receptor concentrations. In rats, inhibition of sphingosine kinase attenuates acute lung injury after hemorrhagic shock. Synthesized lipids and even cholesterol can compensate for depressed calcium-entry following trauma.

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The Role of Systemic Immune Cell Signaling in Whole Body Ischemia/Reperfusion (I/R) injury (Hemorrhagic Shock)
Alfred Ayala, PhD, Division of Surgical Research/Department of Surgery, Rhode Island Hospital/Warren Alpert School of Medicine at Brown University, aayala@lifespan.org

Each year in the United States, trauma kills 150,000 people, mostly young adults. One third of these deaths occur in the hospital as a result of organ failure or sepsis. Both organ failure and sepsis are closely linked to the body’s immune system. If trauma causes the immune system to become over-activated, excessive inflammation can fatally damage organs, but if the immune system is slow to fire up, the body can be overwhelmed by infection. Understanding the cellular signaling pathways involved in the immune response to shock may help doctors prevent trauma victims from succumbing to organ failure and sepsis.

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Autocrine Regulation of Immune Cell Function
Wolfgang G. Junger, PhD, Visiting Professor in Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Department of Surgery, wjunger@ucsd.edu 

Calcium plays a major signaling role in many cells in the body, and cells maintain large (50,000-fold) calcium gradients across their plasma membranes. Although neutrophils are classified as non-excitable cells because their membrane calcium channels are not voltage-gated, calcium signals are very important to neutrophil functions ranging from chemotaxis to apoptosis.

Calcium signaling involves many pathways. In one, G-protein coupled receptors on the cell surface activate a cascade of messengers that leads to the release of calcium stored in the endoplasmic reticulum. This calcium release, in turn, triggers surface channels to allow external calcium to enter the cell. In many types of cells, calcium-entry disorders cause disease, including severe combined immunodeficiency.

Many membrane lipid derivatives, such as sphingosine-1-phosphate, promote external calcium entry, and all these lipid messengers are suppressed by trauma. These messengers seem to work by altering lipid raft composition, which affects membrane curvature and receptor concentrations. In rats, inhibition of sphingosine kinase attenuates acute lung injury after hemorrhagic shock. Synthesized lipids and even cholesterol can compensate for depressed calcium-entry following trauma.

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Translational application of cell signaling biology to the care of sick patients / Panel Discussion

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