Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar




Скачать 197.13 Kb.
НазваниеChapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar
страница3/10
Дата12.10.2012
Размер197.13 Kb.
ТипДокументы
1   2   3   4   5   6   7   8   9   10

CELLULAR EFFECTS



Depending on the magnitude of the insult and the compensatory ability of the cells, the response at the cellular level may be one of compensation, dysfunction, or death. The aerobic respiration apparatus of the cell (i.e., oxidative phosphorylation by mitochondria), is the most susceptible to inadequate oxygen delivery to the tissues. As oxygen tension within cells decreases, there is a decrease in oxidative phosphorylation and the generation of adenosine triphosphate (ATP) slows or stops. When oxygen delivery is impaired so severely that mitochondrial respiration cannot be sustained, the state is called "dysoxia."24 The loss of ATP has widespread effects on cellular function and morphology. As oxidative phosphorylation slows, the cells shift to anaerobic glycolysis that allows for the production of ATP from the breakdown of cellular glycogen. Unfortunately, anaerobic glycolysis is much less efficient than oxygen-dependent mitochondrial pathways. Under aerobic conditions, pyruvate, the end-product of glycolysis, is fed into the Krebs cycle for further oxidative metabolism. Under hypoxic conditions, the mitochondrial pathways of oxidative catabolism are impaired, and pyruvate is instead converted into lactate. The accumulation of lactic acid and inorganic phosphates is accompanied by a reduction in pH, resulting in intracellular metabolic acidosis.

Decreased intracellular pH (intracellular acidosis) can alter the activity of cellular enzymes, lead to changes in cellular gene expression, impair cellular metabolic pathways, and impede cell membrane ion exchange.25 Acidosis also leads to changes in cellular calcium (Ca2+) metabolism and Ca2+-mediated cellular signaling which alone can interfere with the activity of specific enzymes and cell function. These changes in the normal cell function may progress to cellular injury or cell death.

As cellular ATP is depleted under hypoxic conditions, the activity of the membrane Na+,K+-ATPase slows, and thus the maintenance of cellular membrane potential and cell volume is impaired.9,11 Na+ accumulates intracellularly, while K+ leaks into the extracellular space. The net gain of intracellular sodium is accompanied by a gain in intracellular water and the development of cellular swelling. This influx is associated with a reduction in extracellular fluid volume. Endoplasmic reticulum swelling is the first ultrastructural change seen in hypoxic cell injury. Eventually, mitochondrial and cell swelling is observed. The changes in cellular membrane potential impair a number of cellular physiologic processes that are dependent on the membrane potential, such as myocyte contractility, cell signaling, and the regulation of intracellular Ca2+ concentrations. Once intracellular organelles such as lysosomes or cell membranes rupture, the cell will undergo death by necrosis.

Hypoperfusion and hypoxia can induce cell death by apoptosis as well. Animal models of shock and ischemia-reperfusion have demonstrated apoptotic cell death in lymphocytes, intestinal epithelial cells, hepatocytes, and other cells.26 Apoptosis has been detected in trauma patients with ischemia-reperfusion injury, where both lymphocyte and intestinal epithelial cell apoptosis occur in the first 3 hours of injury. The intestinal mucosal cell apoptosis may compromise bowel integrity and lead to translocation of bacteria and endotoxins into the portal circulation during shock. Lymphocyte apoptosis also has been hypothesized to contribute to the immune suppression that is observed in trauma patients.

As cells become hypoxic and ATP-depleted, other ATP-dependent cell processes are affected, such as synthesis of enzymes and structural proteins, repair of DNA damage, and intercellular signal transduction. Tissue hypoperfusion also results in decreased availability of metabolic substrates and the accumulation of metabolic by-products, some of which may be toxic to cells.

Tissue hypoperfusion and cellular hypoxia result not only in intracellular acidosis, but also in systemic metabolic acidosis as metabolic by-products of anaerobic glycolysis exit the cells. The systemic changes in acid/base status may lag behind changes at the tissue level (Fig. 4-8). In the setting of acidosis, the oxyhemoglobin dissociation curve is shifted toward the right. The decreased affinity of hemoglobin in erythrocytes for oxygen results in increased O2 release and increased tissue extraction of oxygen. In addition, hypoxia stimulates the production of erythrocyte 2, 3-diphosphoglycerate (2, 3-DPG), further contributing to the right shift of the oxyhemoglobin dissociation curve, promoting O2 availability to the tissues during shock.

Epinephrine and norepinephrine have a profound impact on cellular metabolism. Hepatic glycogenolysis, gluconeogenesis, ketogenesis, skeletal muscle protein breakdown, and adipose tissue lipolysis are increased by catecholamines. Cortisol, glucagon, and ADH also contribute to the catabolism during shock. Epinephrine induces further release of glucagon, while inhibiting the pancreatic -cell release of insulin. The result is a catabolic state with glucose mobilization, hyperglycemia, protein breakdown, negative nitrogen balance, lipolysis, and insulin resistance during shock and injury. The relative underutilization of glucose by peripheral tissues preserves it for the glucose-dependent organs such as the heart and brain.

In addition to induction of changes in cellular metabolic pathways, shock also induces changes in cellular gene expression. The DNA binding activity of a number of nuclear transcription factors is altered by hypoxia and the production of oxygen radicals or nitrogen radicals that are produced at the cellular level by shock. Expression of other gene products such as heat-shock proteins, vascular endothelial growth factor (VEGF),Au: Ed. Pls check these correction. inducible nitric oxide synthase (iNOS), and cytokines also is clearly increased by shock. Many of these shock-induced gene products, such as cytokines, have the ability themselves to subsequently alter gene expression in specific target cells and tissues.27 The involvement of multiple pathways emphasizes the complex, integrated, and overlapping nature of the response to shock.
1   2   3   4   5   6   7   8   9   10

Похожие:

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconBrittany Graham, Carrie Holl, Brian Fry, and Brian Popp

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconAbel, Andrew B., Macroeconomics / Andrew B. Abel, Ben S. Bernanke, Dean Croushore,2011

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconLt. Governor timothy P. Murray

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconLt. Governor timothy P. Murray

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconLt. Governor timothy P. Murray

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconName timothy J. Gay Date of birth

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconThe 5th International Workshop on Shock/Vortex Interaction The Kaohsiung Grand Hotel

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconChapter 2 70 Effect of novel nop receptor ligands on ethanol drinking in the alcohol-preferring msP rats Chapter 3 96

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconService statute, in Title 42 Chapter 6A to Chapter 1, to repeal

Chapter Shock Andrew B. Peitzman, Brian G. Harbrecht, Timothy R. Billiar iconChapter one brought to the screen the underground world of American muscle cars and dangerous street racing from the City of Angels. Chapter two told a tale of

Разместите кнопку на своём сайте:
Библиотека


База данных защищена авторским правом ©lib.znate.ru 2014
обратиться к администрации
Библиотека
Главная страница