Biologic control of injury and inflammation: much more than too little or too late.
A generalized host inflammatory response is necessary to orchestrate the maintenance or recovery of tissue repair and immune competence following severe injury or infection. When excessive in initial magnitude or duration, however, these otherwise beneficial inflammatory processes may eventuate in deterioration rather than restoration of homeostasis. Although the adverse consequences of excessive inflammatory stimuli may be acutely evident, their influences are more often insidious. A complex cascade of endogenously derived proinflammatory mediators are currently hypothesized to be responsible for both the beneficial and the adverse sequelae of infection and injury. The cytokine proteins tumor necrosis factor and interleukin 1 have been most widely studied as potential targets for antagonist intervention in both experimental models and prospective clinical trials. Preclinical evidence supporting these approaches is briefly discussed herein, as are the results of clinical trials attempting to modulate cytokine influences in the presence of sepsis. The present discussion focuses on potential insights gained from these investigations and the evolving appreciation for the importance of cytokine counterregulatory mechanisms. Examples of potentially complex interactions between inflammatory cytokines and infection-induced antagonist proteins or counterregulatory hormones are provided. It is hypothesized that a sustained imbalance among these proinflammatory and counterregulatory influences may be a critical determinant of outcome in patients with severe infection.
Guirao
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Department of Surgery, Laboratory of Surgical Metabolism, New York Hospital, Cornell University Medical College, 525 East 68 Street, New York, New York 10021, U.S.A.
Lowry
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SF
D000818:Animals; D002986:Clinical Trials as Topic; D003422:Critical Care; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007121:Immunocompetence / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D009102:Multiple Organ Failure / Q000401:mortality / Q000503:physiopathology* / Q000628:therapy; D009104:Multiple Trauma / Q000401:mortality / Q000503:physiopathology* / Q000628:therapy; D015996:Survival Rate; D016896:Treatment Outcome; D014945:Wound Healing / Q000502:physiology
D016207:Cytokines; D018836:Inflammation Mediators