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EDITORIAL FOCUS
INFLAMMATION AND CYTOKINES
Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
IN THE 14 YEARS SINCE the landmark report from the Institute of Medicine (17), much has been learned about the role of gender in patient outcomes. Women typically have lower mortality rates than men from many chronic diseases at any age (5). An increasing amount of data have described a sexual dimorphism in response to acute injury, attributed to a beneficial effect of the female hormone estrogen and a deleterious effect of the male hormone testosterone. This concept has been confirmed in a variety of models from neutered or intact rodents with gender-specific agonists or antagonists in hormone-repleted or depleted conditions (e.g., see Refs. 1, 13, 15).
Hsu et al. (14) have designed an especially elegant study to investigate the mechanism by which gender influences organ function after trauma. In male rats, they demonstrate that administration of estradiol normalized injury-induced changes in intestinal myeloperoxidase, lactate, inflammatory cytokines, ICAM-1, cytokine-induced neutrophil chemoattractant-1, macrophage inflammatory protein-2, and intestinal p38 MAPK activity but not heme oxygenase. However, an inhibitor of p38 MAPK abolished the anti-inflammatory effects of estradiol as well as the increase in heme oxygenase.
These findings, in context with accumulated evidence, show how sex hormones shape the host response to injury and further support the theoretical potential that hormone manipulation might improve adverse pathophysiological conditions following trauma. However, the famous philosopher Yogi Berra observed that "In theory, there's no difference between theory and practice. In practice, there is." (3). Apparently that observation applies to gender and trauma.
Table 1 shows outcome results from tens of thousands of patients evaluating the influence of gender on pathophysiologic responses after major trauma. Even a brief glance reveals an entire spectrum of responses. For example, in over 13,000 patients with severe head injury, an identical pattern of improved outcomes in postmenopausal but not premenopausal females vs. age-matched males was observed. These authors concluded that endogenous female sex hormone production was not neuroprotective (7).
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In the largest experience to date (>36,000 blunt trauma patients), a multivariate logistic regression analysis definitively established that gender was not independently associated with mortality (16).
Altogether, the data in Table 1 suggest that, unlike rodents, gender offers no obvious survival advantage in humans following trauma. Why? There is no disputing that 1) trauma alters immune function, 2) immune-competent cells can generate and respond to sex hormones, and 3) hormone levels change after trauma/sepsis. This reviewer proposes at least four potential explanations, all related to the relevance of laboratory model vs. the real-life situation. These explanations should be considered in context: "That's why I can explain it. If I understood it, I wouldn't know anything about it." (3).
In a syngeneic rodent model, Hsu et al. (14) produced trauma with a midline abdominal incision superimposed on a controlled arterial hemorrhage to 40 mmHg for 90 min, followed by a fixed-volume crystalloid resuscitation but no other cardiopulmonary support. In contrast, in the genetically diverse groups of patients in Table 1, there was no typical severe injury per se. Any trauma victim with an injury severity score >15 probably had massive soft tissue injury in more than one body region (by definition), but may or may not have had massive blood loss and probably required large and variable amounts of intravenous fluids and blood products, mechanical ventilation, supplemental oxygen, and/or several different drugs, and could spend prolonged periods in recovery and rehabilitation. The manner in which these conditions could have confounded any effect of gender can be summarized as follows.
First, there is ample evidence that there is a fundamental difference in homeostatic compensatory response to uncontrolled hemorrhage, or volume, or pressure-matched controlled hemorrhage (21) and profound changes in the pituitary-adrenal axis and the renin-angiotensin system, depending on rate, type, and volume of fluid administered for resuscitation (22, 23). Whereas the patients in Table 1 may have suffered massive blood loss in addition to hypothermia, hypoxia, hypotension, acidosis, coagulopathy, etc, the rats did not. The influence of these other conditions on gender-related, and other endocrine homeostatic responses to trauma cannot be underestimated.
Second, there is substantial evidence that the composition of the indigenous flora plays an important role in modulating outcome in animal models of shock and sepsis (25). Certain strains and species of bacteria disseminate from the intestinal tract more easily than others, antibiotic-induced alterations of the flora can modulate the incidence of systemic spread, and a certain threshold number of intestinal bacteria facilitates extraintestinal dissemination. Since cytokine or neuroendocrine responses to shock vary depending on whether the animal is germ-free, conventionally reared in the laboratory, or in wild-type or farm conditions, it is not surprising that the gender-related effects on septic complications in a syngeneic rodent population might not necessarily predict those in a genetically diverse population of trauma patients.
Third, there are valuable lessons about basic physiological and pathophysiological mechanisms in humans from the perspective of comparative physiology (19), but certain specific responses are often more clearly visible in some species than in humans. Rodents, in particular, have evolved to cope with some extreme environmental conditions and, as a consequence, they have developed efficacious adaptive responses, in essence functioning as "biological amplifiers" to extend fertility and to assure survival of the fittest with highest fertility (4). These adaptive responses depend on close and integrated cooperation of the neuroendocrine and cytokine regulatory systems but do not necessarily confer an evolutionary advantage in humans.
Finally, in patients, unlike rodents, estrogen and testosterone levels depend on several uncontrolled factors, such as social history (e.g., smoking, alcohol, and illicit drug use), transfusions, degree of injury severity, and genetic predisposition. All these factors will alter immune function and likely outcomes from trauma, as much, if not more than, gender (16).
In summary, a mechanism is proposed for gender-related differences in response to trauma (14). These results significantly contribute to the state of the art and are likely to have far-reaching implications for understanding the role of gender in basic and applied situations. The practical significance is less obvious, but future clinical trials should probably stratify patients by gender hormone levels, age, and magnitude of injury to more fully understand complications and death after major trauma. It is clear that a number of factors influence outcomes in trauma patients, that controlling as many variables as possible is necessary for meaningful data interpretation, and "... it ain't over 'til it's over."
FOOTNOTES
Address for reprint requests and other correspondence: K. G. Proctor, Daughtry Family Dept. of Surgery, Univ. of Miami Miller School of Medicine (D40), Ryder Trauma Center, 1800 N.W. 10th Ave. Suite 215, Miami, FL 33136 (e-mail: kproctor{at}miami.edu)
REFERENCES
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