PATHOPHYSIOLOGY OF SEPTIC SHOCK AND IMPLICATIONS FOR THERAPY

Current knowledge about the pathophysiology of septic shock is reviewe d, and biotechnology-based therapies under development are discussed. Patients with septic shock begin their clinical course with leukocytos is, fever, tachycardia, tachypnea, and organ hypoperfusion; shock ensu es as immunologic and vasoactive mediators produce hypotension. There are many metabolic and cardiovascular responses, and single- or multip le-organ failure is common. Patients may experience adult respiratory distress syndrome. A multitude of endogenous and exogenous factors hav e been linked to the pathophysiology of sepsis and septic shock, inclu ding (1) endotoxin from gram-negative bacteria, (2) peptidoglycan and exotoxins from gram-negative bacteria, (3) endotoxin-binding proteins and receptors, (4) bactericidal proteases, (5) exotoxins from gram-pos itive bacteria, (6) acute-phase proteins and proteases, (7) cytokines, (8) arachidonic acid metabolites, (9) complement, (10) beta-endorphin , (11) histamine, (12) stimulation of intrinsic and extrinsic coagulat ion pathways and proteases, and (13) endothelium-derived factors and a dhesion molecules. Molecular entities and strategies under development to combat septic shock include monoclonal antibodies to endotoxin, ac tive immunization with lipid-A analogues, bactericidal permeability-in creasing protein, interleukin inhibitors, and inhibitors of tumor necr osis factor-alpha. Successful treatment of septic shock will probably require a combination of agents, including antimicrobials. An ideal go al for biotechnology in the area of septic shock is to prevent invadin g pathogens from overstimulating the host's immune system and to syste matically eliminate those pathogens. Biotechnology is opening new aven ues to the treatment of septic shock.