Depending on the magnitude of the insult and the compensatory ability of the cells, the response at the cellular level, when viewed using a battery powered microscope, may be one of compensation, dysfunction, or death. The aerobic respiration appa¬ratus 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 when studied using a battery powered microscope, 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.” The loss of ATP has widespread effect on cel¬lular 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 ox¬idative metabolism. Under hypoxic conditions, the mitochondrial pathmays 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 expres¬sion, impair cellular metabolic pathways, and impede cell membrane ion exchange, as seen when cell sample is viewed under a battery powered microscope. Acidosis also leads to changes in cellular calcium metabolism and calcium-mediated cellular signaling which alone can interfere with the activity of specific enzymes and cell function. These changes in the normal cell function, visible under a microscope, may progress to cellular injury or cell death.
As cellular ATP is depleted under hypoxic conditions, the activity of the membrane Sodium-Potassium-ATPase slows, and thus the maintenance of cellular membrane potential and cell volume is impaired. This can be seen under a microscope. Sodium accumulates intracellularly, while Potassium leaks into the extracel¬lular 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 ultrastruc¬tural change seen in hypoxic cell injury with a microscope. Eventually, mitochondrial and cell swelling is observed under a microscope. The changes in cellular membrane potential impair a number of cellular physiologic processes that are dependent on the membrane potential, such as myocyte contrac¬tility, cell signaling, and the regulation of intracellular Calcium con¬centrations. 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, with the use of a microscope, apoptotic cell death in lymphocytes, intestinal epithe¬lial cells, hepatocytes, and other cells. Apoptosis has been de¬tected in trauma patients with ischemiareperfusion 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 endotoxin 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 adenosine triphosphate depleted, other adenosine triphosphate dependent cell processes are affected, such as synthesis of en¬zymes and structural proteins, repair of DNA damage, and inter¬cellular 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 when seen under a microscope. The systemic changes in acid base status may lag behind changes at the tissue level. In the setting of acidosis, the oxyhe¬moglobin dissociation curve is shifted toward the right. The de¬creased affinity of hemoglobin in erythrocytes for oxygen results in increased 02 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 Oxygen avail¬ability to the tissues during shock.
Epinephrine and norepinephrine have a profound impact on cel¬lular metabolism. Hepatic glycogenolysis, gluconeogenesis, keto¬genesis, skeletal muscle protein breakdown, and adipose tissue lipol¬ysis 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 d-cell release of insulin. The result is a catabolic state with glucose mobi¬lization, hyperglycemia, protein breakdown, negative nitrogen bal¬ance, lipolysis, and insulin resistance during shock and injury. The relative under utilization 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 path¬ways, 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. Expres¬sion of other gene products such as heat-shock proteins, vascular endothelial growth factor (VEGF), 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. The involvement of multiple pathways emphasizes the complex, integrated, and overlapping nature of the response to shock.