Clinical review: Immunodepression in the surgical patient and increased susceptibility to infection
© BioMed Central Ltd 2002
Published: 24 May 2002
Several studies indicate that organ failure is the leading cause of death in surgical patients. An excessive inflammatory response followed by a dramatic paralysis of cell-mediated immunity following major surgery appears to be responsible for the increased susceptibility to subsequent sepsis. In view of this, most of the scientific and medical research has been directed towards measuring the progression and inter-relationship of mediators following major surgery. Furthermore, the effect of those mediators on cell-mediated immune responses has been studied. This article will focus on the effect of blood loss and surgical injury on cell-mediated immune responses in experimental studies utilizing models of trauma and hemorrhagic shock, which have defined effects on the immunoinflammatory response. Subsequently these findings will be correlated with data generated from surgical patients. The results of these studies may generate new approaches for the treatment of immunodepression following major surgery, thus reducing the susceptibility to infection and increasing the survival rate of the critical ill surgical patient.
Keywordsimmunodepression infection surgery
Several studies indicate that organ failure is the leading cause of death in surgical patients . Most cases of multiple organ dysfunction are precipitated by infection. Nonetheless, the outcome of organ dysfunction does not correlate well with the microbiology of multiple organ dysfunction syndrome . Several studies indicate that a causal relationship exists between the surgical or traumatic injury and the predisposition of these patients to develop septic/infectious complications and/or multiple organ failure [3,4,5]. The excessive inflammatory response, together with a dramatic paralysis of cell-mediated immunity following major surgery [3,6], appears to be responsible for the increased susceptibility to subsequent sepsis.
In view of this, most of the scientific and medical research has been directed towards measuring the progression and inter-relationship of mediators that are activated or suppressed following major surgery. In most clinical studies alterations in immune parameters of patients following surgery have been assessed due to evaluation of peripheral blood cell function and plasma levels of various mediators. Therefore, animal models have been utilized that simulate the clinical conditions. This has allowed us to better define the pathophysiology of the immunoinflammatory response following surgical trauma, which reduces the patient's capability to resist subsequent life-threatening infectious complications.
This article will focus on the effect of blood loss and surgical injury on cell-mediated immune responses in experimental studies utilizing models of trauma and hemorrhagic shock, which have defined effects on the immunoinflammatory response. Subsequently each paragraph will discuss how the findings from these experimental studies correlate with data generated from surgical patients. The effect of surgeries on the susceptibility to polymicrobial sepsis and infection will then be illustrated. These studies may generate new approaches for the treatment of immunodepression following major surgery, thus reducing the susceptibility to infection and increasing the survival rate of the critical ill surgical patient.
Macrophage function following surgery
Macrophage cytokine release
Altered host defense mechanisms after major surgery or trauma are considered important for the development of infectious complications and sepsis. Immune deterioration has also been reported in patients after trauma and surgery. In this respect, studies have shown areactivity of circulating monocytes towards stimulation with bacteria or endotoxin following surgical trauma . This paralysis of monocyte cell function has been reported to persist for three to five days after trauma  and appears to be a potential risk factor for postoperative septic complications .
In contrast, other studies demonstrate an enhanced secretion of IL-1β and IL-10 by endotoxin-stimulated peripheral blood monocytes at different time points after surgery . Differences in the severity of the surgical trauma might account for those divergent results.
In addition to cytokine release patterns, a high acute physiology and chronic health evaluation (APACHE) II score was associated with an increased number of proinflammatory CD14+ CD16+ monocytes . Furthermore, high levels of CD14+ CD16+ monocytes remained in patients with persistently high APACHE II scores .
Macrophage antigen presentation following major surgery
Antigen presentation is defined as a process whereby a cell expresses antigen on its surface in a form capable of being recognized by a T cell. The proteinaceous antigen typically undergoes some form of processing in which it is degraded into small peptides that are capable of associating with MHC class II antigen for presentation to helper T lymphocytes or in association with MHC class I antigen to become a target for cytotoxic T lymphocytes . However, for competent antigen presentation to take place, the antigen-presenting macrophage must provide a second costimulatory signal, in the form of a membrane and/or soluble factor. Impaired monocyte function and disruption of monocyte/T cell interaction have been shown to be crucial for the development of septic complications in surgical patients . It this respect, human leukocyte antigen (HLA-DR) receptor expression is depressed in some surgical patients and correlates with sepsis severity and outcome . Furthermore, a significant shift toward Fc receptor monocyte subsets can be found. This subpopulation resembles activated macrophages characterized by high proinflammatory cytokine synthesis and suppressed antigen presentation. Similarly, Wakefield et al. demonstrated that an earlier recovery of the depressed HLA-DR expression was associated with a lower rate of septic complications .
It should be noted that a normal or enhanced capacity of peripheral blood monocytes to present bacterial superanti-gens and to stimulate T cell proliferation after surgery has been found despite decreased HLA-DR antigen presentation . These changes were evident despite a significant loss of cell surface HLA-DR molecules. Thus, the level of MHC class II protein expression does not necessarily predict the antigen-presenting capacity of monocytes obtained from surgical patients with uneventful postoperative recovery .
Moreover, MacLean et al.  and Christou et al.  have reported that the outcome of trauma patients is worsened when they exhibit a depressed, delayed-type hypersensitivity reaction (which is antigen specific). Thus, depressed cell-mediated immunity in patients following injury or major surgery, which is associated with an increased mortality from subsequent sepsis [16,17] is probably due, in part, to decreased antigen-presenting capacity by macrophages.
These above findings collectively suggest that the depression of macrophage antigen presentation capacity following injury or major surgery is an important contributory factor to the depression of cell-mediated immunity, thereby, increasing subsequent susceptibility to infection. Interestingly, multiple factors (which include decreased metabolic activity, anti-inflammatory cytokines, prostaglandins and nitric oxide) appear to be responsible for the depression of macrophage antigen-presenting capacity.
These changes in macrophage function appear to be irreversible. Therefore, we treated patients undergoing major surgery with 15 g granulocyte colony stimulating factor (G-CSF) perioperatively, which reduced the acute inflammatory response. This anti-inflammatory effect of G-CSF might contribute to the normalization of the depressed lipopolysaccharide-induced cytokine release by monocytes following major surgery. Moreover, administration of G-CSF normalized the depressed HLA-DR expression in surgical patients. It is our hypothesis, that G-CSF induces the release of new, unaltered monocytes postoperatively, thereby preventing immuno-suppression. Whether these effects of G-CSF result in a decreased infection rate following major surgery remains to be determined in a larger clinical trial.
Lymphocyte function following hemorrhagic shock
Both experimental and clinical studies indicate that a wide range of traumatic injuries alter the ability of T lymphocytes to respond to mitogenic activation (by concanavalin A and phytohemagglutinin) [18,19,20,21,22,23]. These studies demonstrate decreased mitogenic response of lymphocytes in patients following general surgery, blunt trauma, and thermal injury [20,21,22,23,24]. Interestingly the degree of lymphocyte depression correlated with the complexity of the surgery. Similarly, following trauma-hemorrhage decreased splenocyte proliferative capacity in response to the T cell mitogen, concanavalin A, has been demonstrated extensively in our laboratory [18,19,25,26]. In addition, Hensler et al. showed a severe defect of T lymphocyte proliferation and cytokine secretion in vitro following major surgery. In these studies, reduced cytokine secretion by T lymphocytes was observed for IL-2, IFN-γ, and tumor necrosis factor α (TNF-α) during the early postoperative course . Monocyte functions, however, were not altered, suggesting a predominant defect in the T cell response rather than an impaired monocyte antigen-presenting capacity. Thus, suppression of T-cell effector functions during the early phase of the postoperative course may define a state of impaired defense against pathogens and increased susceptibility to infection and septic complications.
Similarly, the release of Th1 lymphokines (i.e. IL-2, IFN-γ) by splenocytes has been shown to be significantly depressed as early as two hours following experimental trauma and hemorrhagic shock, simulating surgical trauma [18,19,25,26] and this depression persists for up to five days following trauma-hemorrhage . In contrast to Th1 lymphokines, the release of the anti-inflammatory Th2 lymphokine, IL-10, has been shown to be increased after trauma-hemorrhage in mice . Neutralizing IL-10 by the addition of anti-IL-10 monoclonal antibodies to the culture media restored the depressed splenocyte proliferative capacity in splenocytes harvested from traumatized animals . Moreover, early anti-IL-10 treatment following burn injury prevented T cell immunosuppression and improved the survival rate following subsequent sepsis . Thus, IL-10 following trauma-hemorrhage might contribute to the depressed splenocyte Th1 lymphokine release following trauma and injury. In contrast, van der Poll et al. demonstrated in a model of endotoxemia an increased mortality rate following anti-IL-10 treatment, suggesting protective effects of IL-10 following lipopolysaccharide injection . Depending on the model and the time of administration, anti-IL-10 might exhibit divergent effects on immune responses.
In addition to release patterns, T lymphocyte subsets have been determined in patients with acute illness . These studies indicate that following major surgery, both cell populations decrease. Patients that develop septic complications, however, display a predominant decrease in CD4+cells .
Moreover, changes in B cell function have also been reported following surgical trauma. The capacity of splenic B cells to produce antibodies is significantly decreased following trauma and blood loss [31,32]. In this regard, a decrease in overall serum levels of immunoglobulin was seen for up to three days after surgical trauma and blood loss [31,32]. The decreased IL-2 production by T lymphocytes has been suggested to be responsible for the downregulation of antibody production by B cells following severe injury, since T cell lymphokines are a prerequisite for adequate B cell proliferation and immunoglobulin secretion . Whether restoration of T cell function following severe injury and major surgery, however, restores the depressed B cell function remains to be determined.
Circulatory inflammatory mediators
The observed immunodeficiency in trauma victims and patients following major surgery has been found to be associated with enhanced concentrations of inflammatory cytokines, reflecting activated immunocompetent cells in the patient . Thus, it appears that the depressed cell-mediated immune responses in vitro discussed in the above paragraphs reflect hyporesponsiveness to a second stimulus following massive activation in vivo .
Since in vivo administration of IL-1, IL-6, and TNF-α [44,45,46,47] induces a shock-like syndrome, similar to that observed following severe blood loss and sepsis, it has been suggested that these cytokines may play a role in initiating the cascade of events that can lead to the development of multiple organ dysfunction following severe hemorrhagic shock.
Furthermore, the marked increase in the release of proinflamma-tory cytokines by Kupffer cells following trauma and blood loss in experimental studies has been reported to be associated with depressed immune functions . This suggests that proinflam-matory cytokines produced by Kupffer cells following hemorrhage act in an autocrine as well as a paracrine fashion to downregulate Kupffer cell and other macrophage populations. Furthermore, Kupffer cells, which represent the largest pool of macrophages in the body, were found to release increased amounts of IL-1, IL-6, and TNF-α following shock  and the selective reduction of this macrophage population by injection of gadolinium chloride significantly reduced plasma IL-6 levels following hemorrhage . This leads to the conclusion that Kupffer cells are a significant source of the increased plasma levels of proinflammatory cytokines following trauma and hemorrhage, and these cytokines can act to depress macrophage function. Whether or not Kupffer cells are the only contributors to the enhanced proinflammatory plasma levels following severe injury and major surgery remains to be determined.
In contrast to the early increase of proinflammatory cytokines in the plasma following trauma and shock, elevated plasma levels of the anti-inflammatory cytokine, transforming growth factor (TGF)-β, are not detectable until 24 hours after the insult . Furthermore, this elevation in plasma TGF-β persisted until 72 hours after trauma and hemorrhage . Neutralization of TGF-β antibodies restored the depressed antigen presentation to normal levels . These results, along with the studies by Miller-Graziano et al.  indicate that the enhanced release of TGF-β is an additional factor responsible for the prolonged suppression of macrophage function following hemorrhagic shock.
In addition to pro- and anti-inflammatory cytokines, numerous other mediators in the plasma have been reported to contribute to the depression of cell-mediated immune response following trauma and shock. In this respect, eicosanoids have been extensively studied as agents involved in immunological responses [51,52,53]. Two hours after shock, an increased release of prostaglandins and leukotrienes by macrophages occurs leading to elevated plasma levels of eicosanoids [3,54]. Moreover, prostaglandin E2 has been shown to inhibit cell-mediated immune function [55,56]. Conversely, administration of ibuprofen (an inhibitor of cyclooxygenase) to animals following severe blood loss prevented the depression of macrophage functions . Ayala et al.  have also demonstrated that rodents that were pre-fed a fish oil diet high in omega-3-fatty acids (known to inhibit the synthesis of prostaglandin E2 via inhibition of arachidonic acid metabolism) had normal macrophage functions following hemorrhage.
Increased levels of circulating cytokines have also been reported following a variety of tissue insults in patients, including trauma, sepsis, thermal injury, and surgery [5,40,59,60]. In this regard, increased plasma IL-6 levels in patients have been observed during the first week following trauma . Interestingly, levels of proinflammatory cytokines have been shown to be higher in trauma patients with severe blood loss compared to patients with trauma alone . Moreover, in septic patients the increase of the proinflammatory cytokines IL-6 and TNF-α has been found to be much higher than in trauma victims without septic complications . These findings suggest additive effects of trauma, blood loss, and septic complications on the immunoinflammatory response. Furthermore, proinflammatory cytokine levels, as well as the duration of elevation, appear to correlate with the severity of the insult. In addition, elevated cytokine levels have been shown to persist for five days after gastrectomy, compared to three days after mastectomy . Furthermore, several clinical studies have shown an association between elevated plasma levels of proinflammatory cytokines, increased infectious complications, and higher mortality rates [5,37,61,62,63,64,65]. In this respect, Molloy et al. reported a progressive decline in TNF-α levels in survivors of septic shock, whereas TNF-α levels remained persistently elevated after initial diagnosis and attempted treatment in nonsurvivors from septic shock .
The above studies suggest the important contribution of proinflammatory cytokines to the pathophysiological changes seen in surgical patients and trauma victims. Therefore, determination of proinflammatory cytokine levels might become important for clinicians who encounter a trauma patient in the intensive care unit. Knowledge of the patient's cytokine levels may give him/her some indicator of the intracellular milieu, and possibly insight into cellular changes taking place. This information might give the clinician a better understanding of how to treat such a critically ill trauma patient. More refinements towards the rapid and online measurements of cytokines are needed, however, before the full benefits of such information can be effectively translated to better management of trauma patients. Although various cytokine therapies in septic patients so far have not yielded satisfactory results, the lack of beneficial effects might be related to the timing and dose of anti-cytokine administration. It is our hypothesis that total blockade/neutralization of cytokines will not be helpful to the host. Instead, modulation of cytokine production/release by immune cells (i.e. macrophages, T cells) leading to the restoration of cellular homeostasis might be a better approach for decreasing the susceptibility of trauma victims and patients following major surgery to subsequent sepsis and infection.
Increased susceptibility to infection
The studies mentioned above indicate depressed immunoresponsiveness after trauma and hemorrhage, which persists despite fluid resuscitation. To determine whether these observations translate into an actual reduction in the capacity of these traumatized animals to ward off infection of a clinically relevant nature, additional studies were conducted by Stephan et al. in which sepsis was induced 3 days after hemorrhagic shock . The results demonstrate an increased susceptibility of hemorrhaged animals to polymicrobial sepsis, as evidenced by an increased mortality rate of hemorrhaged animals following subsequent sepsis (mortality of hemorrhaged animals following subsequent sepsis 100% compared to 50% in sham animals subjected to sepsis) [19,67]. Similarly, Zapata-Sirvent et al. have indicated that the mortality rate in response to a septic challenge was increased in mice . Interestingly, restoration of the depressed immune responses following trauma and severe blood loss with immunomodulatory agents, such as flutamide (an androgen receptor blocker), was associated with increased survival rates following subsequent sepsis .
Gender-specific immune responses following trauma, injury, and blood loss
Despite the fact that gender differences in the susceptibility to, and morbidity from, sepsis have been observed in several clinical and epidemiological studies [70,71,72,73], little attention has been paid to gender when studying immune responses in surgical and trauma patients. Furthermore, experimental studies investigating alterations in immune functions following trauma have used predominantly male laboratory animals. Recent studies initiated by Zellweger et al. , however, examined immune functions in female rodents following the induction of sepsis by cecal ligation and puncture. The results demonstrated maintenance of splenocyte function in females when they were in the proestrus stage of the estrus cycle, as opposed to depression of splenocyte function in males following cecal ligation and puncture . Furthermore, the preservation of immune responses in females was also associated with higher survival rates following the induction of sepsis . Subsequently, further studies were conducted investigating the effect of gender on cell-mediated immunity following injury and blood loss. In particular, females in the proestrus state showed enhanced IL-1 and IL-6 release by splenic and peritoneal macrophages, and splenocyte IL-2 and IL-3 release, as opposed to depressed macrophage and splenocyte functions in males under such conditions . Higher plasma estradiol and/or higher plasma prolactin levels in proestrus females might contribute to the enhanced immune responses following hemorrhage in proestrus females. Furthermore, administration of estrogen to castrated male mice that were supplemented with testosterone improved the depressed immune responses in those animals . In addition, treatment of male mice with estradiol normalized the depressed immune responses after trauma and hemorrhage and improved the survival rate following subsequent sepsis . Since estradiol replacement therapy is associated with an increased rate of thromboembolism, this therapy is not useful in surgical patients . Such complications, however, have not been reported with regard to the steroid hormone dehydroepiandrosterone, which has been reported to display estrogenic effects . Moreover, treatment of male mice following trauma and blood loss prevented immunosuppression . Since dehydroepiandrosterone is used clinically as a long-term immunoenhancing drug in humans, this hormone might represent a useful therapy for preventing immunodepression in surgical patients.
In addition to female sex steroids, the lower levels of male hormones in female animals compared to males might also contribute to the divergent immunoresponsiveness following injury and blood loss. Support for the importance of male sex hormones in producing the immune depression in males following hemorrhage comes from recent studies indicating that castration of male mice two weeks prior to hemorrhage prevented the depression of splenic and peritoneal macrophages following the hemorrhagic insult [76,81]. Moreover, depletion of testosterone by castration prior to hemorrhage normalized the IL-6 release by Kupffer cells following hemorrhage [76,81]. In attempting to address whether testosterone per se is responsible for the depressed macrophage functions following hemorrhage in males, studies were conducted in which castrated male mice were treated with 5α-dihydrotestosterone prior to trauma-hemorrhage . The results demonstrated that castrated male mice treated with testosterone (which had higher plasma testosterone levels than intact males) displayed similar immune responses to hemorrhage to those shown by intact males, namely depression of splenic and peritoneal macrophage function . Similarly, treatment of female mice with 5α-dihydrotestosterone also depressed splenic and peritoneal macrophage function as well as splenocyte responses [25,82]. In addition, gender-specific immune responses have also been demonstrated in the thymus, the primary location of T cell lymphopoiesis . The exact mechanism, however, for the immunomodulatory properties of male and female sex steroids following trauma-hemorrhage remains unknown.
Similar observations have been obtained in clinical trials following sepsis, surgery, or trauma and blood loss. In this regard, Bone demonstrated, in a retrospective study incorporating four major sepsis studies, a preponderance of morbidity and mortality in males compared to females . McGowan et al. also reported a significantly higher incidence of bacteremic infections in males than in females . A recent prospective study by Schröder et al. confirms that gender differences were observed in human sepsis, with a significantly better prognosis for women . Hospital-mortality rate in this study was 70% for male compared to 26% for female patients following the induction of sepsis. Similarly, following injury, male gender has been shown to be a risk factor for the development of septic complications and pneumonia [84,85,86].
In summary the above studies suggest that gender, as well as the state of the estrus cycle in females, should be taken into consideration in designing not only experimental but also clinical studies concerning immune responses following trauma and shock. Moreover, the results of these studies suggest that administration of sex steroids or treatment with their specific blockers should be considered as a novel and useful approach for modulating the immune responses in those patients.
The above studies indicate that injury, trauma, and blood loss produce a marked suppression in cell-mediated immunity and an increased susceptibility to subsequent sepsis and wound infection. Furthermore, global as well as differential effects can be observed on macrophages that are dependent on their anatomical location. The use of a variety of immunomodulatory agents (e.g. dilitiazem, chloroquine, ibuprofen, IFN-γ, prolactin, metclopramide, and flutamide) have been shown to be helpful for the normalization of the altered immune responses following trauma and hemorrhage in experimental studies. The success in the use of immunomodulatory agents following hemorrhage in rodent models appears to be promising in the development of new therapeutic concepts for the treatment of immunosuppression and for decreasing the mortality from subsequent sepsis in humans. However, careful evaluation of both the benefits and potential adverse effects of therapy is needed before widespread clinical use can be envisioned. Recently, administration of G-CSF perioperatively has been shown to prevent immunosuppression following major surgery. The enhanced release of new, unaltered monocytes appears to be responsible for the immunoenhancing effects of G-CSF. Larger clinical trials should be initiated to verify that the immunoprotective effects of G-CSF are associated with a decreased susceptibility of surgical patients to infectious complications, thereby decreasing the mortality rate.
The immunoinflammatory response, and subsequent sepsis, is still one of the major causes of morbidity and mortality following major surgery. While significant advances have been made, it is important to further define the pathophysiology and identify the precise mechanisms responsible for the depression of the cell-mediated immunity using experimental animal models. However, these animal models should take into consideration the various manipulations that the patient receives as well as the effect of gender, nutritional status, pre-existing conditions etc. Effective treatment regimes for patients can only be developed when models of injury begin to consider these factors.
APACHE = acute physiology and chronic health evaluation
ELISA = enzyme-linked immunosorbent assay
G-CSF = granulocyte colony stimulating factor
IFN = interferon
MHC = major histocompatibility complex
TGF = transforming growth factor
Th = T helper.
- Carrico CJ, Meakins JL, Marshall JC: Multiple organ failure syndrome. Arch Surg 1986, 121: 196-208.View ArticlePubMedGoogle Scholar
- Stahl GL, Bitterman H, Terashita Z, Lefer AM: Salutary consequences of blockade of platelet activating factor in hemorrhagic shock. Eur J Pharmacol 1988, 149: 233-240. 10.1016/0014-2999(88)90653-XView ArticlePubMedGoogle Scholar
- Chaudry IH, Ayala A: Immunological Aspects of Hemorrhage. Austin: Medical Intelligence Unit, RG Landes Company; 1992.Google Scholar
- Stephan RN, Ayala A, Chaudry IH: Monocyte and lymphocyte responses following trauma. In Pathophysiology of Shock, Sepsis and Organ Failure. (Edited by: Schlag G, Redl H). Berlin: Springer-Verlag 1993, 131-144.View ArticleGoogle Scholar
- Roumen RM, Hendriks T, van der Ven-Jongekrijg J, Nieuwenhuijzen GAP, Sauerwein RW, van der Meer JW, Goris RJA: Cytokine patterns in patients after major surgery, hemorrhagic shock, and severe blunt trauma. Ann Surg 1993, 6: 769-776.View ArticleGoogle Scholar
- Faist E, Baue AE, Dittmer H: Multiple organ failure in poly-trauma patients. J Trauma 1983, 23: 775-787.View ArticlePubMedGoogle Scholar
- Haupt W, Riese J, Mehler C, Weber K, Zowe M, Hohenberger W: Monocyte function before and after surgical trauma. Dig Surg 1998, 15: 102-104. 10.1159/000018601View ArticlePubMedGoogle Scholar
- Faist E, Storck M, Hultner L, Redl H, Ertel W, Walz A, Schildberg FW: Functional analysis of monocytes activity through synthesis patterns of proinflammatory cytokines and neopterin in patients in surgical intensive care. Surgery 1992, 112: 562-572.PubMedGoogle Scholar
- Hensler T, Ecker H, Eeg K, Eidecke CD, Artels H, Arthlen W, Agner H, Iewert JR, Olzmann B: Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun 1997, 65: 2283-2291.PubMed CentralPubMedGoogle Scholar
- Fingerle-Rowson G, Auers J, Kreuzer E, Fraunberger P, Blumenstein M, Ziegler-Heitbrock LH: Expansion of CD14+CD16+ monocytes in critically ill cardiac surgery patients. Inflammation 1998, 22: 367-379. 10.1023/A:1022316815196View ArticlePubMedGoogle Scholar
- Ayala A, Ertel W, Chaudry IH: Trauma-induced suppression of antigen presentation and expression of major histocompati-bility class II antigen complex in leukocytes. Shock 1996, 5: 79-90.View ArticlePubMedGoogle Scholar
- Schinkel C, Sendtner R, Zimmer S, Faist E: Functional analysis of monocyte subsets in surgical sepsis. J Trauma 1998, 44: 743-748.View ArticlePubMedGoogle Scholar
- Wakefield CH, Carey PD, Foulds S, Monson JR, Guillou PJ: Changes in major histocompatibility complex class II expression in monocytes and T cells of patients developing infection after surgery. Br J Surg 1993, 80: 205-209.View ArticlePubMedGoogle Scholar
- MacLean LD, Meakins JL, Taguchi K, Duignan J, Dhillon KS, Gordon J: Host resistance in sepsis and trauma. Ann Surg 1975, 182: 207-211.PubMed CentralView ArticlePubMedGoogle Scholar
- Christou NV, Tellado JM: The impact of preexisting disease conditions for host defense integrity in traumatized and critically ill patients. In Host Defense Dysfunction in Trauma, Shock and Sepsis. (Edited by: Faist E, Meakins J, Schildberg FW). Berlin-Heidelberg: Springer-Verlag 1993, 73-82.View ArticleGoogle Scholar
- Levy EM, Alharbi SA, Grindlinger G, Black PH: Changes in mitogen responsiveness lymphocyte subsets after traumatic injury: relation to development of sepsis. Clin Immunol Immunopathol 1984, 32: 224-233.View ArticlePubMedGoogle Scholar
- Keane RM, Birmingham W, Shatney CM, Winchurch RA, Munster AM: Prediction of sepsis in the multitraumatic patient by assays of lymphocyte responsiveness. Surg Gynecol Obstet 1983, 156: 163-167.PubMedGoogle Scholar
- Ayala A, Lehman DL, Herdon CD, Chaudry IH: Mechanism of enhanced susceptibility to sepsis following hemorrhage: interleukin (IL)-10 suppression of T-cell response is mediated by eicosanoid induced IL-4 release. Arch Surg 1994, 129: 1172-1178.View ArticlePubMedGoogle Scholar
- Stephan RN, Kupper TS, Geha AS, Baue AE, Chaudry IH: Hemorrhage without tissue trauma produces immunosuppression and enhances susceptibility to sepsis. Arch Surg 1987, 122: 62-68.View ArticlePubMedGoogle Scholar
- Riddle PR, Berenbaum MC: Postoperative depression of the lymphocyte response to phytohaemagglutinin. Lancet 1967, i: 746-748.View ArticleGoogle Scholar
- O'Mahony JB, Palder SB, Wood JJ, McIrvine A, Rodrick ML, Demling RH, Mannick JA: Depression of cellular immunity after multiple trauma in the absence of sepsis. J Trauma 1984, 24: 869-875.View ArticlePubMedGoogle Scholar
- Daniels JC, Sakai H, Cobb EK, Lewis SR, Larson DL, Ritzmann SE: Evaluation of lymphocyte reactivity studies in patients with thermal burns. J Trauma 1971, 11: 595-607.View ArticlePubMedGoogle Scholar
- Sakai H, Daniels JC, Lewis SR, Lynch JB, Watson DL, Ritzmann SE: Reversible alterations of nucleic acid synthesis in lymphocytes after thermal burns. J Reticuloendothelial Soc 1972, 11: 19-28.Google Scholar
- Abraham E, Chang YH: The effects of hemorrhage on mitogen-induced lymphocyte proliferation. Circ Shock 1985, 15: 141-149.PubMedGoogle Scholar
- Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH: Testosterone: the culprit for producing splenocyte depression following trauma-hemorrhage. Am J Physiol 1998, 274: C1530-C1536.PubMedGoogle Scholar
- Zellweger R, Ayala A, DeMaso CM, Chaudry IH: Trauma-hemorrhage causes prolonged depression in cellular immunity. Shock 1995, 4: 149-153.View ArticlePubMedGoogle Scholar
- Lyons A, Goebel A, Mannick JA, Lederer JA: Protective effects of early interleukin 10 antagonism on injury-induced immune dysfunction. Arch Surg 1999, 134: 1317-1323. 10.1001/archsurg.134.12.1317View ArticlePubMedGoogle Scholar
- van der Poll T, Marchant A, Buurman WA, Berman L, Keogh CV, Lazarus DD, Nguyen L, Goldman M, Moldawer LL, Lowry SF: Endogenous IL-10 protects mice from death during septic peritonitis. J Immunol 1995, 155: 5397-5401.PubMedGoogle Scholar
- Feeney C, Bryzman S, Kong L, Brazil H, Deutsch R, Fritz LC: T-lymphocyte subsets in acute illness. Crit Care Med 1995, 23: 1680-1685. 10.1097/00003246-199510000-00012View ArticlePubMedGoogle Scholar
- O'Mahony JB, Wood JJ, Rodrick ML, Mannick JA: Changes in T lymphocyte subsets following injury. Assessment by flow cytometry and relationship to sepsis. Ann Surg 1985, 202: 580-586.PubMed CentralView ArticlePubMedGoogle Scholar
- Abraham E, Freitas AA: Hemorrhage in mice induces alterations in immunoglobulin-secreting B-cells. Crit Care Med 1989, 17: 1015-1019.View ArticlePubMedGoogle Scholar
- Abraham E, Freitas AA: Hemorrhage produces abnormalities in lymphocyte function and lymphokine generation. J Immunol 1989, 142: 899-906.PubMedGoogle Scholar
- Fuchs D, Gruber A, Wachter H, Faist E: Activated cell-mediated immunity and immunodeficiency in trauma and sepsis. In The Immune Consequences of Trauma, Shock and Sepsis. Mechanisms and Therapeutic Approaches. (Edited by: Faist E, Baue AE, Schildberg FW). Lengerich: Pabst Science Publishers 1996, 235-239.Google Scholar
- Fuchs D, Malkovsky M, Reibnegger G, Werner ER, Forni G, Wachter H: Endogenous release of interferon-gamma and diminished response of peripheral blood mononuclear cells to antigenic stimulation. Immunol Lett 1989, December 23: 103-108. 10.1016/0165-2478(89)90120-XView ArticleGoogle Scholar
- Ayala A, Perrin MM, Meldrum DR, Ertel W, Chaudry IH: Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin. Cytokine 1990, 2: 170-174.View ArticlePubMedGoogle Scholar
- Ayala A, Wang P, Ba ZF, Perrin MM, Ertel W, Chaudry IH: Differential alterations in plasma IL-6 and TNF levels following trauma and hemorrhage. Am J Physiol 1991, 260: R167-R171.PubMedGoogle Scholar
- Damas P, Reuter A, Gysen P, Demonty J, Lamy M, Franchimont P: Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med 1989, 17: 975-978.View ArticlePubMedGoogle Scholar
- Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M: Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992, 215: 356-362.PubMed CentralView ArticlePubMedGoogle Scholar
- Romagnani S: Th1 and Th2 in human diseases. Clin Immunol Immunopathol 1996, 80: 225-235. 10.1006/clin.1996.0118View ArticlePubMedGoogle Scholar
- Martin C, Boisson C, Haccoun M, Thomachot L, Mege JL: Patterns of cytokine evolution (tumor necrosis factor-α and interleukin-6) after septic shock, hemorrhagic shock, and severe trauma. Crit Care Med 1997, 25: 1813-1819. 10.1097/00003246-199711000-00018View ArticlePubMedGoogle Scholar
- Ertel W, Morrison MH, Ayala A, Perrin MM, Chaudry IH: Anti-TNF monoclonal antibodies prevent haemorrhage-induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression. Immunology 1991, 74: 290-297.PubMed CentralPubMedGoogle Scholar
- Porteu F, Nathan C: Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med 1990, 172: 599-607.View ArticlePubMedGoogle Scholar
- Ertel W, Morrison MH, Ayala A, Chaudry IH: Chloroquine attenuates hemorrhagic shock induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression through blockade of tumor necrosis factor and prostaglandin release. Blood 1991, 78: 1781-1788.PubMedGoogle Scholar
- Wong GC, Clark SC: Multiple actions of interleukin 6 within a cytokine network. Immunol Today 1988, 9: 137-139. 10.1016/0167-5699(88)91200-5View ArticlePubMedGoogle Scholar
- Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA: Interleukin-1 induces a shock like state in rabbits. Synergism with tumor necrosis factor and the effects of cyclooxygenase inhibition. J Clin Invest 1988, 81: 1162-1172.PubMed CentralView ArticlePubMedGoogle Scholar
- Tracey KJ, Lowry SF, Fahey TJI, Albert JD, Fong Y, Hesse D, Beutler B, Manogue KR, Calvano S, Wei H, Cerami A, Shires GT: Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet 1987, 164: 415-422.PubMedGoogle Scholar
- Lejeune P, Lagadec P, Onier N, Pinnard D, Ohshima H, Jeannin JF: Nitric oxide involvement in tumor-induced immunosuppression. J Immunol 1994, 152: 5077-5083.PubMedGoogle Scholar
- O'Neill PJ, Ayala A, Wang P, Ba ZF, Morrison MH, Schultze AE, Reich SS, Chaudry IH: Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation. Shock 1988, 1: 43-47.View ArticleGoogle Scholar
- Ayala A, Meldrum DR, Perrin MM, Chaudry IH: The release of transforming growth factor-β following hemorrhage: its role as a mediator of host immunosuppression [abstract]. FASEB J 1992, 6: A1604.Google Scholar
- Miller-Graziano CL, Szabo G, Griffey K, Metha B, Kodys K, Catalano D: Role of elevated monocyte transforming growth factor beta (TGF-beta) production in posttrauma immunosuppression. J Clin Immunol 1991, 11: 95-102.View ArticlePubMedGoogle Scholar
- Waal Malefyt R, Abrams J, Bennett B, Figdor CG, Vries JE: Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991, 174: 1209-1220.View ArticlePubMedGoogle Scholar
- Faist E, Mewes A, Baker CC, Strasser T, Alkan SS, Rieber P, Heberer G: Prostaglandin E 2 dependent suppression of interleukin-2 production in patients with major trauma. J Trauma 1987, 27: 837-848.View ArticlePubMedGoogle Scholar
- Knapp W, Baumgartner G: Monocyte-mediated suppression of human B lymphocyte differentiation in vitro. J Immunol 1978, 121: 1177-1183.PubMedGoogle Scholar
- Johnston PA, Selkurt EE: Effect of hemorrhagic shock on renal release of prostaglandin E. Am J Physiol 1976, 230: 831-838.PubMedGoogle Scholar
- Bonta IL, Parnham MJ: Immunomodulatory-antiinflammatory functions of E-type prostaglandins. Minireview with emphasis on macrophage mediated effects. Int J Immunopharmacol 1982, 4: 103-109. 10.1016/0192-0561(82)90057-1View ArticlePubMedGoogle Scholar
- Plaut M: The role of cyclic AMP in modulating cytotoxic T lymphocytes. I. In vivo-generated cytotoxic lymphocytes, but not in vitro-generated cytotoxic lymphocytes, are inhibited by cyclic AMP-active agents. J Immunol 1979, 123: 692-701.PubMedGoogle Scholar
- Chaudry IH, Ayala A: Immune consequences of hypovolemic shock and resuscitation. Curr Opin Anaesthesiology 1993, 6: 385-392.View ArticleGoogle Scholar
- Ayala A, Chaudry IH: Dietary n-3 polyunsaturated fatty acid modulation of immune cell function pre- or post-trauma. Nutrition 1995, 11: 1-11.PubMedGoogle Scholar
- Beutler B: Tumor necrosis factor and other cytokines in septic syndrome. In Sepsis. (Edited by: Vincent JL). Berlin: Springer-Verlag 1994, 107-121.View ArticleGoogle Scholar
- Shirakawa T, Tokunaga A, Onda M: Release of immunosuppressive substances after gastric resection is more prolonged than after mastectomy in humans. Int Surg 1998, 83: 210-214.PubMedGoogle Scholar
- Feldbush TL, Hobbs MV, Severson CD, Ballas ZF, Weiler JM: Role of complement in the immune response. Fed Proc 1984, 43: 2548-2552.PubMedGoogle Scholar
- Marks JD, Marks CB, Luce JM, Montgomery B, Turner J, Metz CA, Murray JF: Plasma tumor necrosis factor in patients with septic shock. Am Rev Respir Dis 1990, 141: 94-97.View ArticlePubMedGoogle Scholar
- Marano MA, Fong Y, Moldawer LL, Wei H, Calvano SE, Tracey KJ, Barie PS, Manogue K, Cerami A, Shires GT, Lowry SF: Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet 1990, 170: 32-38.PubMedGoogle Scholar
- Waage A, Halstensen A, Espevik T: Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987, i: 355-357. 10.1016/S0140-6736(87)91728-4View ArticleGoogle Scholar
- Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T: The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 1989, 169: 333-338.View ArticlePubMedGoogle Scholar
- Molloy RG, Mannick JA, Rodrick ML: Cytokines, sepsis and immunomodulation. Br J Surg 1993, 80: 289-297.View ArticlePubMedGoogle Scholar
- Angele MK, Wichmann MW, Ayala A, Cioffi WG, Chaudry IH: Testosterone receptor blockade after hemorrhage in males: restoration of the depressed immune functions and improved survival following subsequent sepsis. Arch Surg 1997, 132: 1207-1214.View ArticlePubMedGoogle Scholar
- Zapata-Sirvent RL, Hansbrough JF, Cox MC, Carter WH: Immunologic alterations in a murine model of hemorrhagic shock. Crit Care Med 1992, 20: 508-517.View ArticlePubMedGoogle Scholar
- Simons RK, Hoyt DB, Winchell RJ, Rose RM, Holbrook T: Elevated selectin levels after severe trauma: a marker for sepsis and organ failure and a potential target for immounomodula-tory therapy. J Trauma 1996, 41: 653-662.View ArticlePubMedGoogle Scholar
- Bone RC: Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 1992, 268: 3452-3455. 10.1001/jama.268.24.3452View ArticlePubMedGoogle Scholar
- Center for Disease Control: Mortality Patterns – United States, 1989. MMWR 1992, 41: 121-125.Google Scholar
- McGowan JE, Barnes MW, Finland N: Bacteremia at Boston City Hospital: occurrence and mortality during 12 selected years (1935–1972) with special reference to hospital-acquired cases. J Infect Dis 1975, 132: 316-335.View ArticlePubMedGoogle Scholar
- Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F: Gender differences in human sepsis. Arch Surg 1998, 133: 1200-1205. 10.1001/archsurg.133.11.1200View ArticlePubMedGoogle Scholar
- Zellweger R, Ayala A, Stein S, DeMaso CM, Chaudry IH: Females in proestrus state tolerate sepsis better than males. Crit Care Med 1997, 25: 106-110. 10.1097/00003246-199701000-00021View ArticlePubMedGoogle Scholar
- Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Chaudry IH: Enhanced immune responses in females as opposed to decreased responses in males following hemorrhagic shock. Cytokine 1996, 8: 853-863. 10.1006/cyto.1996.0114View ArticlePubMedGoogle Scholar
- Angele MK, Knoferl MW, Ayala A, Cioffi WG, Bland K, Chaudry IH: Male and female sex steroids: do they produce deleterious or beneficial effects on immune responses following trauma-hemorrhage? Surg Forum 1998, 49: 43-45.Google Scholar
- Knoferl MW, Diodato MD, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH: Do female sex steroids adversely or beneficially affect the depressed immune responses in males after trauma-hemorrhage? Arch Surg 2000, 135: 425-433. 10.1001/archsurg.135.4.425View ArticlePubMedGoogle Scholar
- Mannucci PM: Venous thromboembolism and hormone replacement therapy. Eur J Intern Med 2001, 12: 478-483. 10.1016/S0953-6205(01)00169-8View ArticlePubMedGoogle Scholar
- Catania RA, Angele MK, Ayala A, Cioffi WG, Bland K, Chaudry IH: Dehydroepiandrosterone (DHEA) restores immune function following trauma-hemorrhage by a direct effect on T-lymphocytes. Cytokine 1998, 11: 443-450. 10.1006/cyto.1998.0458View ArticleGoogle Scholar
- Angele MK, Catania RA, Ayala A, Cioffi WG, Bland K, Chaudry IH: Dehydroepiandrosterone (DHEA): an inexpensive steroid hormone which decreases the mortality from sepsis. Arch Surg 1998, 133: 1281-1288. 10.1001/archsurg.133.12.1281View ArticlePubMedGoogle Scholar
- Wichmann MW, Ayala A, Chaudry I: Male sex steroids are responsible for depressing macrophage immune function after trauma-hemorrhage. Am J Physiol 1997, 273: C1335-C1340.PubMedGoogle Scholar
- Angele MK, Ayala A, Monfils BA, Cioffi WG, Bland KI, Chaudry IH: Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma 1998, 44: 78-85.View ArticlePubMedGoogle Scholar
- Angele MK, Xu YX, Ayala A, Catania RA, Cioffi WG, Bland KI, Chaudry IH: Gender differences in immune responses: increased thymocyte apoptosis occurs only in males but not in females after trauma-hemorrhage. Surg Forum 1997, 48: 95-97.Google Scholar
- Gannon CJ, Napolitano LM, Pasquale M, Tracy K, McCarter RJ: Male gender increases risk of postinjury pneumonia. Surg Forum 2001, 52: 468-469.Google Scholar
- Offner PJ, Moore EE, Biffl WL: Male gender is a risk factor for post-injury major infections [abstract]. In Proceedings of the 19th Meeting of the Surgical Infection Society 1999, 20.Google Scholar
- Oberholzer A, Keel M, Trentz O, Ertel W: Die inzidenz von septischen komplikationen nach polytrauma ist geschlechts-spezifisch [abstract]. Hefte zu Der Unfallchirurg 63. Jahrestagung der Deutschen Gesellschaft fuer Unfallchirurgie: 1999, 231-232.Google Scholar