Inflammation, Sepsis and Multiorgan Dysfunction
MODS is the most common cause of death in critically ill patients but its pathogenesis and pathobiology are poorly understood. The Stavropoulos Sepsis Research Program, directed by Clifford Deutschman, MD, managed by Nichelle Raj, MS, and funded by a generous gift from Bill and Linda Stavropoulos, is charged with studying mechanisms of regulatory dysfunction in this period in the hope of identifying and examining unique therapeutic approaches. Excessive inflammation can damage normal tissue and thus impair normal organ function. One example of this is the adult respiratory distress syndrome (ARDS), a common pathologic condition induced by sepsis, that effects the lungs. Work by Yoram Weiss, MD, MBA, Senior Lecturer in Anesthesiology and Critical Care Medicine at Hadassah Hebrew University Medical Center in Jerusalem, Israel and Adjunct Associate Professor of Anesthesiology and Critical Care at Penn and Dr. Deutschman has uncovered some important molecular and cellular abnormalities that may precipitate ARDS. Many involve a deficiency in the expression of intracellular chaperone molecules collectively called heat shock proteins (HSPs). These findings have suggested novel therapeutic approaches that include the use of adenoviral-mediated gene therapy to replace the deficient 70kDs HSP70. This approach has been quite effective in mice. Melanie Lyons, a graduate student, is examining alternative approach with delivery of HSP70 via the HIV-derived TAT protein. Resident Jason Brainard, MD, and medical student Jonathan Dunkman have developed a novel xenon delivery system and are examining the ability of this gas, which protect ischemic brain, to limit ARDS by a mechanisms that involve HSP70. Additional work in collaboration with Laurie Kilpatrick, PhD, Professor of Physiology and Director of Research for the Lung Biology Center at Temple University has focused on tissue-damaging inflammatory cells called neutrophils. Dr. Kilpatrick has been performing in vitro studies using a unique neutrophil inhibitor called delta Protein Kinase C (dPKC). She recently has used the TAT protein to deliver dPKC into the lungs of septic mice with promising results. A final aspect of ARDS research involves collaboration with the Dept. of Radiology. Maurizio Cereda MD and Dr Deutschman, in collaboration with Rahim Rizi PhD are using hyperpolarized helium to investigate lung mechanics and ventilation/perfusion (V/Q) abnormalities in experimental ARDS. This involves MRI scanning of the lungs of septic mice. The experiments will determine how therapeutic approaches (HSP70, dPKC etc) alter V/Q and if there is improvement. Unlike ARDS, most of the abnormalities induced by sepsis do not involve tissue destruction. Rather, they arise in the face of excessive inflammation but rapidly progress to organ dysfunction. Among these are cellular and molecular abnormalities leading to hepatic dysfunction. Dr. Deutschman and Kenneth M. Andrejko, DO, have been studying the effects of sepsis on the liver for a number of years. Recent investigations have centered on the inflammatory cytokine interleukin (IL) – 6, released by inflammatory cells into tissue or blood. The work has demonstrated that the ability of IL-6 to modulate hepatic function becomes impaired fairly early in sepsis. This involves a block in the intracellular signaling pathway by which extracellular IL-6 alters activity within liver cells. Recent work by Drs. Andrejko and Deutschman and Ms Raj with medical student Arney Abcejo, research fellows Albert Ruggieri and Erin McGuire and post-doc Ifeanyi Nwaneshiudu, MD, has demonstrated that the block involves impaired phosphorylation of the intracellular signaling molecule gp130. Based on investigations initiated by Richard Levy, MD, (see below) Laura Lee, MD, Assistant Professor of Pediatrics at the University of Virginia, found an impairment in hepatic mitochondria that might underlie the altered phorphorylation. This is being explored further by Dr. Nwaneshiudu and Mr. Ruggieri. Drs. Deutschman and Andrejko have also demonstrated that severe sepsis impairs regeneration of liver cells, a process that is IL-6 dependent. In conjunction with Mark Clemens, PhD, Professor of Biology and Vice Chair for Research at the University of North Carolina – Charlotte, the use of excess IL-6 as therapy is being explored. Finally, Dr Deutschman and Max Kelz, MD, PhD, are generating mice capable of deleting the IL-6 gene in the liver in response to treatment with a protein called Cre Recombinase. This allows for conditional elimination of IL-6 in the liver, which should shed further light on the sepsis-induced defect. The studies on the liver are funded by the NIGMS (5R01GM059930-08 and 5R21AI070929-02). Cardiac dysfunction is an important component of both sepsis and MODS. Studies by Dr. Deutschman and Richard Levy, MD, Associate Professor of Anesthesiology and Pediatrics at the George Washington University, Director of Cardiac Anesthesia at Childrens National Medical Center and Adjunct Assistant Professor of Anesthesiology and Critical Care at Penn, have examined the role of mitochondrial dysfunction in cardiac dysfunction from sepsis and ischemia. It is well-known that ischemic cardiac tissue, such as is found after an heart attack, reduces its activity to a minimal level to preserve remaining tissue. This process is called “hibernation” and appears to be adaptive. Drs. Levy and Deutschman uncovered a similar effect in early sepsis. They discovered that the activity of cytochrome oxidase, the rate-limiting step in the mitochondrial electron transport chain, is inhibited shortly after the induction of sepsis in mice. In mild sepsis this dysfunction resolves. However, in severely septic mice who progress to develop MODS, the block becomes more profound and is associated with a loss of the proteins that make up cytochrome oxidase. This is followed by a loss of the mitochondria themselves. Normally mitochondria replace themselves, a process called biogenesis. However, biogenesis appears to become impaired in MODS. Interestingly, Dr Levy found that the administration of cytochrome C reversed the early abnormality seen in mitochondrial and cardiac function. This suggested a novel potential therapeutic approach. Residents Alison Perate, MD, and Amy Reed, MD, PhD, in conjunction with Surgery Resident Hooman Noorchashm, MD, PhD, Ali Naji, MD, PhD, Professor of Surgery and Dr. Deutschman are exploring the effects of sepsis on inflammatory cells called B-lymphocytes. This has been a neglected area in sepsis research and is quite promising. Another perplexing aspect of sepsis and MODS are the effects on the endocrine system. In particular, the effects of both endogenous and exogenous glucocorticoids, such as cortisol, have generated a great deal of controversy. Recent investigations by John Cidlowski, PhD, of the NIH, have revealed the presence of multiple isoforms of the intracellular receptors that bind cortisol and modulate its activity. These different isoforms are generated by post-transcription modification of a single mRNA. In a new collaboration Drs. Cidlowski and Deutschman, along with medical student Robert Eberhardt and resident Jessica Dworet, MD, PhD, have begun examining how sepsis effects the relative abundance of these isoforms and ho post-transcription processes are altered. Finally, the MODS syndrome involves abnormalities of cardiac and pulmonary function, altered temperature regulation, an impaired mental status with failed arousal and a profound depression of most of the endocrine system. Recent work has uncovered a small nexus of neurons in the hypothalamus that secrete a neurotransmitter called orexin. The orexinergic system connects to and modulates centers that control all of the above-described abnormalities. Drs. Kelz and Deutschman, along with Ms. Raj and resident Jon Anson, MD, have found that the activity of the orexinergic system is significantly decreased in septic mice. We will soon begin exploring a number of exciting therapeutic approaches. |
Inflammation is part of the characteristic response to tissue injury. While most perioperative inflammation is adaptive, promoting healing and recovery, in some circumstances the process becomes pathological. In addition, prolonged inflammation soon gives way to a prolonged, highly stable but highly abnormal state. This later is characterized by depressed function in nearly all organ systems. The syndrome of excessive inflammation is referred to as either “the Systemic Inflammatory Response Syndrome (SIRS)” or “sepsis” while the ensuing depressed organ function is called “the multiple organ dysfunction syndrome (MODS)”.