J. Kent Trinkle, MD
University of Texas Health Science Center, San Antonio, Texas
1. Basic scientists have answers to most clinical problems - but they don't know the questions.
2. Clinicians have the questions - but can't talk to the basic scientists.
3. Most human illness and injury elicits a generic stress response involving the endothelial cell, neutrophil and platelet; and evil humors that they generate.
4. This generic stress response is humoral and causes end-organ dysfunction.
5. The response can be modified and therefore treated if we understand the basic mechanisms.
There is a complex cellular and molecular generic response to injury leading to multiorgan failure. This response is frequently magnified and diagnosed in the lung as the acute respiratory distress syndrome (ARDS) because the lung is a very delicate and unforgiving organ. Also, the pulmonary injury is easily identified and quantitated by radiographs, arterial blood gases, arteriovenous shunt, lung compliance, pulmonary artery and vein pressures and cardiac output as measured by a Swan-Ganz catheter.
The systemic response to stress has been called the Systemic Inflammatory Response Syndrome (SIRS). SIRS may occur in hypovolemia, sepsis, cardiopulmonary bypass and either blunt or penetrating trauma. The process of ischemia and reperfusion of an organ or tissue has interesting molecular sequelae. The interaction of the neutrophil and the endothelial cell, governed by inflammatory cytokines, adhesion molecules, and the generation of free radicals, has been implicated in the development of SIRS. Restoration of blood flow exacerbates the injury due to the generation of oxygen free radicals during reperfusion. There are two basic techniques to prevent free radical injury. One is to prevent formation and the second is to "mop up" the radicals which have been generated. Drugs such as glutathione and superoxide dismutase have shown limited clinical and experimental efficacy as free radical scavengers. Neutrophils play an active role in SIRS by becoming activated and adherent to the endothelium. It has been shown that with aortic cross clapping and ischemia of the lower extremities there is a rapid infiltration of neutrophils after reperfusion. A similar phenomenon occurs in myocardial infarction and stroke and systemically in response to hypovolemic shock. The adhesion of the neutrophil with the endothelial cell initiates this inflammatory response. Therapeutic attempts to degrease circulating neutrophils to limit this response have met with moderate success. Other attacks have been on the adhesion molecules (intercellular adhesion molecule [ICAM]-1 and P-selectin) to inhibit the adherence of the neutrophil to the endothelial cell. Each of these attempts to interrupt the interaction of the neutrophil and endothelial cell; thus limiting cytokine and free radical generation, have met with limited clinical and experimental success. This approach may be the wave of the future.
The key to organ integrity is the endothelial cell which normally maintains a dynamic process of vasoconstriction and dilatation and governs permeability of the capillary wall. The capillary continuously undergoes a process of filtration and reabsorption of fluid and solutes. The factors promoting filtration, or loss of fluid into the tissue, are the capillary hydrostatic pressure and the tissue oncotic pressure. Conversely, reabsorption of fluid and solutes is governed by tissue hydrostatic pressure and capillary oncotic pressure.
Multiorgan dysfunction following major trauma is described in up to 20% of patients. Actually, the true figure is probably 100% depending on the sensitivity of the criteria, and the organ involved. With lung dysfunction, hypoxemia (PO2 below 200 mmHg, FiO2 100%), decreased compliance, increased permeability, diffuse alveolar damage on radiograph or transbronchial biopsy, with a pulmonary capillary wedge pressure below 17 mmHg is diagnosed as ARDS. Many of these changes are reversible with the proverbial "pound of cure," but perhaps could have been prevented at an earlier stage.
Following major trauma, there is an increase in capillary permeability and edema, both systemic and pulmonary, which is frequently compounded with iatrogenic overhydration. Blunt chest trauma, either with or without head injury, results in a neurogenic response or a sympathetic neural discharge, which decreases both pulmonary and peripheral vascular resistance and increases cardiac output. There is an additional increase in the right and left ventricular ejection fraction, which along with the increased cardiac output, tends to injure the endothelial cell due to shear stress. Patients with multiple trauma likewise have decreased surfactant on bronchoalveolar lavage, even without chest injury. With hypovolemic shock there is a process of microvascular pulmonary artery occlusion with platelets and leukocytes that precipitate a vicious cycle of endothelial cell injury and permeability. Likewise, within the parenchyma of the organs there is leukocyte sequestration with an increase in tumor necrosis factor-?, interleukin-1 and interleukin-2, all of which contribute to endothelial cell dysfunction.
The major metabolic response to trauma revolves around the relationship of the neutrophil and the endothelial cells, which are governed by adhesion molecules called integrins and selectins. The ultimate inflammatory response occurs when the neutrophil migrates out of the capillary. The process starts with activation of the neutrophil so that it becomes stiff, adheres to the endothelial cell and ultimately migrates through the endothelium. After migration there is permanent injury to endothelial cells by humoral mediators, as well as oxygen free radicals, cytokines, and proteases. This exposes the basement membrane of the capillary, increasing thrombogenicity, permeability, and vascular tone because of a loss of production of nitric oxide (NO), which leads to generalized organ and tissue dysfunction. The activated neutrophil creates reactive oxygen metabolites, that cause direct cellular oxidant injury to lipids, proteins, and DNA by superoxide, hydroxyl , and hydrogen peroxide radicals. This process of activation and cellular oxidant production causes permanent structural damage to endothelial cells and end organs.
Endothelial cell dysfunction is the critical early event in the body's molecular response to injury. Within minutes superoxide radicals are produced by both the endothelial cell and the neutrophil. The adhesion molecules on the neutrophil react with their ligands on the activated endothelial cells by attaching like a magnet. There is then a second generation of radicals, cytokines, and proteases released when the neutrophil adheres to the endothelium. At this point there is a decrease in the endothelial cell relaxation factor which is now known to be NO.
The endothelial cell possesses various protective mechanisms. The first is prostacycline, a vasodilator that decreases both neutrophil adhesion and platelet aggregation. Additionally, the prostacyclines stabilize the lysosome membrane and activate adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP). Other vasodilators have been tried both experimentally and therapeutically without success, because the protective mechanism of prostacycline is not just vasodilatation, but cytoprotective via cAMP.
The endothelium also depends on NO production to balance pulmonary vascular resistance. NO has a biological half-life of 10 to 20 seconds and is a calcium and calmodulin-dependent system. L-Arginine is the precursor of NO and, under the influence of NO synthase, NO is produced. NO activates guanylate cyclase which in turn produces cyclic guanosine monophosphate (cGMP), which inactivates superoxide radicals, creates vasodilatation, and decreases neutrophil adherence and platelet aggregation.
A third protective mechanism is the production of adenosine, another rapidly metabolized compound. Adenosine produces vasodilatation and reduces neutrophil adherence and cytotoxicity as well as neutralizing superoxide radicals. It also decreases potassium induced intracellular calcium loading as occurs during cardioplegia.
The endothelium also has certain proinflammatory, or self-destructive, tendencies that cause vasoconstriction and thrombosis. The first is endothelin-1 (E-1), which in the face of hypoxia causes vasoconstriction and thrombosis. Infusion of an E-1 antagonist decreases capillary injury. In patients with ARDS, there is a dramatic increase immeasurable E-1 levels, not only in the lung, but in other organs.
Another proinflammatory substance is platelet activating factor (PAF), which is produced by the endothelial cells in response to sheer stress and hypoxia. PAF causes vasoconstriction and stimulates neutrophil migration and superoxide production, ultimately enhancing vascular permeability and microvascular thrombosis. This process is enhanced by the loss of intrinsic heparin and tissue plasminogen activator production; and the expression of tissue factor by the endothelial cell.
The critical application of the basic facts just elucidated revolved around preserving endothelial cell integrity and function. This both the initial and final common pathway in generic organ dysfunction in stress.
Future investigations and therapy will revolve around prostacycline, exogenous nitric oxide donors and adenosine in addition to free radical scavengers and monoclonal antibodies to block adhesion molecules and cytokines.
