Post-traumatic Immunosuppression Research Articles

Research progress of acupuncture in the regulation of surgery stress response.

In clinical practice, operative stress varies from surgeries, which may lead to many injuries such as ischemia-reperfusion injury (IRI), hyperactivation of sympathetic nervous system (SNS), post-traumatic immunosuppression (PTI), hypercoagulation and inflammation. Acupuncture is effective and advantageous in regulating the stress response to surgery. The great progress has been made in recent years of acupuncture research in postoperative visceral IRI, SNS hyperactivation, PTI, hypercoagulation and inflammation. By collecting the relevant evidences of acupuncture in this field, the application value of acupuncture involved in modulating surgical stress response and the progress of mechanism research are explored and summarized.

Engineering a Cortisol Sensing Enteric Probiotic.

Chronic stress can lead to prolonged adrenal gland secretion of cortisol, resulting in human ailments such as anxiety, post-traumatic stress disorder, metabolic syndrome, diabetes, immunosuppression, and cardiomyopathy. Real time monitoring of chronic increases in cortisol and intervening therapies to minimize the physiological effects of stress would be beneficial to prevent these endocrine related illnesses. Gut microbiota have shown the ability to secrete, respond, and even regulate endocrine hormones. One such microbe, Clostridium scindens, responds transcriptionally to cortisol. We engineered these cortisol responsive genetic elements from C. scindens into an enteric probiotic, E. coli Nissle 1917, to drive the expression of a fluorescent reporter allowing for the designing, testing, and building of a robust and physiologically relevant novel cortisol probiotic sensor. This smart probiotic was further engineered to be more sensitive and to respond to elevated cortisol by expressing tryptophan decarboxylase, thereby bestowing the ability to generate tryptamine and serotonin. Here we show that upon cortisol treatment the smart probiotic produces measurable amounts of tryptamine. Accumulated levels of these neuromodulators should improve mood, anxiety, and depression and drive down cortisol levels. Importantly, this work can serve as a model for the engineering of a sense-and-respond probiotic to modulate the gut-brain axis.

Risk factors and prevention of nosocomial pneumonia in polytrauma

Nosocomial pneumonia (NK) is one of the most frequent complications of polytrauma leading to death. Meanwhile, the recommendations on prevention of NK in case of polytrauma have not been specified so far. This is due in large part to the lack of study of the pathophysiology of severe combined trauma. The review presents the results of modern experimental and clinical studies of the effect of shock, immune distress syndrome, posttraumatic immunosuppression, the phenomenon of mutual aggravation of lesions, age, sex, concomitant pathology on the risk of NK in polytrauma. The role of iatrogenic risk factors for NK in polytrauma – intubation of trachea and artificial lung ventilation (AVL), massive hemotransfusions, immobilization, the phenomenon of “second strike” after multiple surgeries has been determined. The most effective measures of NK prevention are reduction of the duration of AVL, prevention of oropharyngeal colonization and aspiration in case of AVL, use of inhalation antibacterial drugs, antishock measures, early mobilization of the patient, the earliest possible stable functional osteosynthesis by minimally traumatic methods. The data on the effectiveness of selective decontamination of intestines, probiotics and glucocorticosteroids for the prevention of NK in polytrauma are inconsistent. A promising area of NK prophylaxis may be the development of agents that regulate the complex mechanisms of immune response to polytrauma and prevent secondary acute lung injury and post-traumatic immunosuppression.

Lymphocyte Immunosuppression and Dysfunction Contributing to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS).

Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4- CD8- double-negative T cells (DN T cells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.

Liver-derived mitochondria drive CD8 T-cell dysfunction, alter purinergic signaling and impair bacterial clearance in the lung in vivo

Abstract Trauma is the leading cause of death in young adults. The pathogenetic mechanisms resulting in posttraumatic immunosuppression with increased susceptibility to infection remain unclear. Mitochondria (MT) are released by cells after trauma and can generate danger molecules, such as extracellular ATP (eATP). The vascular and immune cell ectonucleotidase CD39 scavenges eATP to generate immunosuppressive derivatives such as adenosine. Here, we examined the role of eATP generated by exogenous mitochondria in modulating the immune response and provoking immunosuppression in the context of experimental pneumonia models. ATP probes and MitoSOX revealed that liver-derived MT generate ATP and ROS ex vivo. When injected into recipient mice, MT isolated from mouse liver induced upregulation of CD39 and CD73 expression on circulating CD8 T cells and promoted immune cell exhaustion. Next, wild-type mice were injected intraperitoneally with liver MT, followed by intratracheal instillation of pathogenic S. aureus. Mice receiving MT were unable to clear bacteria, as demonstrated by elevated CFU counts in the bronchoalveolar lavage, when compared to mice with bacterial instillation alone. Histological analysis confirmed more pronounced lung injury with infiltration of inflammatory neutrophils in mice administered both MT and bacteria, when compared to mice instilled only with bacteria. Lastly, the MT injection with concomitant bacteria administration resulted in loss of lung-derived CD8 T-cells. Our data indicate that ATP generation by exogenous mitochondria boost CD39 expression in circulating CD8 T-cells and drive dysfunctional immune responses in mice that result in increased susceptibility to bacterial infection of the lungs.

Gut epithelial cell-derived exosomes trigger posttrauma immune dysfunction.

Exosomes are extracellular vesicles that act as endogenous mediators of the immune response. We have previously shown that exosomes released into mesenteric lymph (ML) following trauma (T)/hemorrhagic shock (HS) induce proinflammatory cytokine production in macrophages and are involved in the pathogenesis of postshock acute lung injury. However, the cellular origin of ML exosomes and their role in the posttrauma immune response remains unclear. We hypothesized that exosomes released from damaged-intestinal epithelial cells contribute to posttrauma immune dysfunction by altering the function of dendritic cells (DCs), key regulators of the adaptive immunity. Male rats underwent cannulation of the femoral artery, jugular vein and ML duct. T/HS was induced by laparotomy and 60 minutes of hemorrhagic shock followed by resuscitation. The ML was collected before (preshock) and after T/HS (post-T/HS) for isolation of exosomes. Surface epitopes of exosomes isolated from ML were assessed by flow cytometry to determine their cellular origin and phenotypic changes. The immunomodulatory effects of ML exosomes on DCs were assessed by Annexin V apoptosis assay, expression of costimulatory molecules, and antigen-presenting capacity to lymphocytes. Exosomes isolated from ML highly expressed CD63 (exosome marker) and epithelial cell-specific marker, suggesting their derivation from intestinal epithelial cells. The expression of immunomodulatory molecules, such as major histocompatibility complex class II and Fas ligand on ML exosomes, was significantly increased after T/HS. Coincubation of DCs with exosomes isolated from ML after T/HS increased DC apoptosis twofold compared with preshock ML exosomes. Furthermore, post-T/HS ML exosomes significantly suppressed lipopolysaccharide-mediated expression of CD80 and CD86 on DCs as well as decreased their antigen-presenting capacity to induce lymphocytes proliferation. Gut epithelial cells release immunomodulatory exosomes into the ML after T/HS and resuscitation. Mesenteric lymph exosomes may be critical mediators of posttraumatic immunosuppression causing depletion and dysfunction of DCs.

An overview of cytokines and heat shock response in polytraumatized patients.

Early after injury, local tissue damage induces a local and systemic inflammatory response that activates the immune system and leads to the development of systemic inflammatory response syndrome (SIRS). This post-traumatic response often results in uncontrolled release of inflammatory mediators and over-activation of the immune system, which occasionally results in multiple organ dysfunction syndrome (MODS). In parallel, a state of immunosuppression develops. This counter-regulating suppression of different cellular and humoral immune functions has been termed "compensatory anti-inflammatory response syndrome (CARS)." Both SIRS and CARS occur simultaneously even in the initial phase after injury. Pro- and anti-inflammatory cytokines have been suggested to play a major role in development of SIRS, although the degree of involvement of the different cytokines is quite disparate. While TNF-α and IL-1β are quite irrelevant for predicting organ dysfunction, IL-6 is the parameter that best predicts mortality. The hyperinflammatory state seems to be the cause of post-traumatic immunosuppression and heat shock proteins (HSPs), which have been proposed as one of the endogenous stimuli for the deterioration of the immune system acting as danger-associated molecular patterns (DAMPs). Extracellular HSPA1A released from injured tissues increase up to ten times immediately after trauma and even more in patients with MODS. It has powerful immune properties that could contribute to post-traumatic immunosuppression through several mechanisms that have been previously described, so HSPs could represent trauma-associated immunomodulatory mediators. For this reason, HSPA1A has been suggested to be a helpful early prognostic biomarker of trauma after severe injury: serial quantification of serum HSPA1A and anti-Hsp70 concentrations in the first hours after trauma is proposed to be used as a predictive biomarker of MODS and immunosuppression development in polytraumatized patients.

Impact of tranexamic acid on coagulation and inflammation in murine models of traumatic brain injury and hemorrhage

BackgroundPosttraumatic coagulopathy and inflammation can exacerbate secondary cerebral damage after traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown clinically to reduce mortality in hemorrhaging and head-injured trauma patients and has the potential to mitigate secondary brain injury with its reported antifibrinolytic and antiinflammatory properties. We hypothesized that TXA would improve posttraumatic coagulation and inflammation in a murine model of TBI alone and in a combined injury model of TBI and hemorrhage (TBI/H). MethodsAn established murine weight drop model was used to induce a moderate TBI. Mice were administered intraperitoneal injections of 10 mg/kg TXA or equivalent volume of saline 10 min after injury. An additional group of mice was subjected to TBI followed by hemorrhagic shock using a pressure-controlled model. TBI/H mice were given intraperitoneal injections of TXA or saline during resuscitation. Blood was collected at intervals after injury to assess coagulation by rotational thromboelastometry (ROTEM) and inflammation by Multiplex cytokine analysis. Soluble P-selectin, a biomarker of platelet activation, and serum neuron-specific enolase, a biomarker of cerebral injury, were measured at intervals. Brain homogenates were analyzed for inflammatory changes by Multiplex enzyme-linked immunosorbent assay, and splenic tissue was collected for splenic cell population assessment by flow cytometry. ResultsThere were no coagulation, serum or cerebral cytokine, P-selectin, or neuron-specific enolase differences between mice treated with TXA or saline after TBI. After the addition of hemorrhagic shock and resuscitation to TBI, TXA administration still did not affect coagulation parameters, systemic or cerebral inflammation, or platelet activation, as compared with saline alone. At 24 hours after TBI, mice given TXA demonstrated lower splenic total cell counts central memory CD8, effector CD8, B cell, and increased naive CD4 cell populations. By contrast, TXA did not affect splenic leukocyte populations after combined TBI/H. ConclusionsDespite clinical data suggesting a mortality benefit, TXA did not modulate coagulation, inflammation, or biomarker generation in either the TBI or TBI/H murine models. Administration of TXA after TBI altered splenic leukocyte populations, which may contribute to a change in posttraumatic immune status. Future studies should be done to investigate the role of TXA in the development of posttraumatic immunosuppression and risk of nosocomial infections.

Sterile post-traumatic immunosuppression.

After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI.

Early inflammatory response in polytraumatized patients: Cytokines and heat shock proteins. A pilot study

IntroductionIn the initial phases after polytrauma there is an hyperinflammatory state that sometimes leads to multiple organ dysfunction syndrome (MODS) and death, and that appears to be responsible for posttraumatic immunosuppression; among the trigger endogenous stimuli, heat shock proteins (HSPs) have been proposed. The objectives of this study were to analyze if some inflammatory mediators can be considered prognostic biomarkers of outcome, and the possible role of HSPA1A in posttraumatic immunosuppression. HypothesisCytokines and HSPs could be early prognostic biomarkers of inflammatory and immune response in polytrauma patients. Materials and methodsA prospective observational descriptive pilot study was carried out, evaluating the early inflammatory and stress response of 18 polytraumatized patients (ISS>16) on hospital admission, at 12hours, 24hours, and 48hours posttrauma. Variable means were compared using non-parametric tests; qualitative and quantitative variables were analyzed using a Spearman's correlation test. ResultsSeven patients met criteria for MODS. Statistically significant changes were recorded in leukocyte count, C-reactive-protein (CRP), IL-6, TNF-α, and IL-1ß concentrations. HSPA1A levels were significantly higher immediately after the accident followed by gradual lowering. Anti-Hsp70 antibodies showed a significant reduction in all the studied time-points. MODS did not influence either plasma levels of leukocytes, fibrinogen, RCP or anti-Hsp70, but patients with MODS had higher plasma levels of IL-6 and TNF-α and a slower decrease of HSPA1A concentrations. DiscussionThe higher serum concentrations of TNF-α and IL-6 found in patients with MODS, suggests a possible role as potential early predictive markers for systemic inflammatory response and clinical complications. The higher levels of HSPA1A in patients with MODS, allows proposing HSPA1A as a useful prognostic trauma biomarker early after severe injury and to consider a “damage control surgery”. The significant reduction in the levels of anti-Hsp70 antibodies could reflect a part of posttraumatic immunosuppression and hydrocortisone treatment might be suggested. Level of evidenceLevel III: case-control study.

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty.

Major trauma increases vulnerability to systemic infections due to poorly defined immunosuppressive mechanisms. It confers no evolutionary advantage. Our objective was to develop better biomarkers of post-traumatic immunosuppression (PTI) and to extend our observation that PTI was reversed by anti-coagulated salvaged blood transfusion, in the knowledge that others have shown that non-anti-coagulated (fibrinolysed) salvaged blood was immunosuppressive. A prospective non-randomized cohort study of patients undergoing primary total knee arthroplasty included 25 who received salvaged blood transfusions collected post-operatively into acid-citrate-dextrose anti-coagulant (ASBT cohort), and 18 non-transfused patients (NSBT cohort). Biomarkers of sterile trauma included haematological values, damage-associated molecular patterns (DAMPs), cytokines and chemokines. Salvaged blood was analysed within 1 and 6 h after commencing collection. Biomarkers were expressed as fold-changes over preoperative values. Certain biomarkers of sterile trauma were common to all 43 patients, including supranormal levels of: interleukin (IL)-6, IL-1-receptor-antagonist, IL-8, heat shock protein-70 and calgranulin-S100-A8/9. Other proinflammatory biomarkers which were subnormal in NSBT became supranormal in ASBT patients, including IL-1β, IL-2, IL-17A, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and annexin-A2. Furthermore, ASBT exhibited subnormal levels of anti-inflammatory biomarkers: IL-4, IL-5, IL-10 and IL-13. Salvaged blood analyses revealed sustained high levels of IL-9, IL-10 and certain DAMPs, including calgranulin-S100-A8/9, alpha-defensin and heat shock proteins 27, 60 and 70. Active synthesis during salvaged blood collection yielded increasingly elevated levels of annexin-A2, IL-1β, Il-1-receptor-antagonist, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-γ, TNF-α, transforming growth factor (TGF)-β1, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α. Elevated levels of high-mobility group-box protein-1 decreased. In conclusion, we demonstrated that anti-coagulated salvaged blood reversed PTI, and was attributed to immune stimulants generated during salvaged blood collection.

Role of p38 mitogen-activated protein kinase in posttraumatic immunosuppression in mice

Patients with multiple injuries surviving the initial insult are highly susceptible to secondary pneumonia, frequently progressing into sepsis and multiorgan failure. However, the underlying mechanisms of posttraumatic immunosuppression are poorly understood. We hypothesized that dysregulated p38 mitogen-activated protein kinase (MAPK) signaling accounts for impaired lung protective immunity in a model of trauma/hemorrhage (T/H) and subsequent pneumococcal pneumonia in mice. C57BL6/N mice were subjected to trauma by midline laparotomy, and T/H was induced by midline laparotomy followed by cannulation of femoral arteries and veins to induce hemorrhage. Subsequently, mice were infected with Streptococcus pneumoniae. In selected experiments, mice were treated with a p38 MAPK inhibitor or vehicle control immediately after induction of T/H. Mice subjected to T/H showed significantly increased p38 MAPK activation in their lungs, which was accompanied by a reduced Escherichia coli phagocytosis by macrophages from T/H mice in vitro and an impaired pneumococcal killing activity of T/H mice in vivo, overall resulting in increased mortality of T/H mice after infection with S. pneumoniae. Application of p38 MAPK inhibitor BIRB796 immediately after T/H induction improved the bacterial phagocytosis activity of macrophages from T/H mice in vitro and lung pneumococcal killing in vivo but did not improve the survival of T/H mice challenged with S. pneumoniae. T/H triggers sustained p38 MAPK activation in the lungs of mice, which attenuates lung macrophage antibacterial activities and renders mice more susceptible to pneumococcal pneumonia. However, no major role for dysregulated p38 MAPK to affect survival of T/H mice after pneumococcal challenge was detected, suggesting that dysregulated p38 MAPK activity may possibly play only a limited role in posttraumatic immunosuppression in mice.

Innate Immune Dysfunction in Trauma Patients

Innate Immune Dysfunction in Trauma Patients

An animal model for open femur fracture and osteomyelitis: Part I

Infection is an everyday problem in orthopaedics and is quite common in open fracture management. To study this process and provide a basis to prevent infection, we developed a model that includes trauma (blunt fracture in the fashion of Bonnarens and Einhorn), surgical stabilization (standardized intramedullary K-wire fixation), and infection (Staphylococcus aureus inoculum). In this two-part study, we found that 10(2) colony-forming units of inoculum produced an optimal infection rate of 90-100%, which substantially challenged the immune system without overwhelming sepsis. We hypothesized that, in traumatic fractures, there is a specific immunological response that may lead to an increased rate of infection. In Part 2, we demonstrated immunosuppression (decreased Interleukin-12 levels) at days 6, 10, and 12 after fracture fixation versus nonfractured control groups (p < 0.05). This study describes a rat model of femur factures with osteomyelitis that allows investigation of posttraumatic immunosuppression.

Biphasic onset of splenic apoptosis following hemorrhagic shock: critical implications for Bax, Bcl-2, and Mcl-1 proteins

IntroductionThe innate immune response to trauma hemorrhage involves inflammatory mediators, thus promoting cellular dysfunction as well as cell death in diverse tissues. These effects ultimately bear the risk of post-traumatic complications such as organ dysfunction, multiple organ failure, or adult respiratory distress syndrome. In this study, a murine model of resuscitated hemorrhagic shock (HS) was used to determine the apoptosis in spleen as a marker of cellular injury and reduced immune functions.MethodsMale C57BL-6 mice were subjected to sham operation or resuscitated HS. At t = 0 hours, t = 24 hours, and t = 72 hours, mice were euthanized and the spleens were removed and evaluated for apoptotic changes via DNA fragmentation, caspase activities, and activation of both extrinsic and intrinsic apoptotic pathways. Spleens from untreated mice were used as control samples.ResultsHS was associated with distinct lymphocytopenia as early as t = 0 hours after hemorrhage without regaining baseline levels within the consecutive 72 hours when compared with sham and control groups. A rapid activation of splenic apoptosis in HS mice was observed at t = 0 hours and t = 72 hours after hemorrhage and predominantly confirmed by increased DNA fragmentation, elevated caspase-3/7, caspase-8, and caspase-9 activities, and enhanced expression of intrinsic mitochondrial proteins. Accordingly, mitochondrial pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were inversely expressed within the 72-hour observation period, thereby supporting significant pro-apoptotic changes. Solely at t = 24 hours, expression of the anti-apoptotic Mcl-1 protein shows a significant increase when compared with sham-operated and control animals. Furthermore, expression of extrinsic death receptors were only slightly increased.ConclusionOur data suggest that HS induces apoptotic changes in spleen through a biphasic caspase-dependent mechanism and imply a detrimental imbalance of pro- and anti-apoptotic mitochondrial proteins Bax, Bcl-2, and Mcl-1, thereby promoting post-traumatic immunosuppression.

Pulmonary contusion causes impairment of macrophage and lymphocyte immune functions and increases mortality associated with a subsequent septic challenge*

Pulmonary contusion is frequently followed by acute respiratory distress syndrome, pneumonia, and sepsis. However, immunologic alterations of circulating and resident immune cell populations contributing to the posttraumatic immunosuppression are poorly understood. We therefore characterized the influence of pulmonary contusion on peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages. To address the significance of the immunosuppression associated with lung contusion, we investigated how the consecutive addition of moderate or severe sepsis affected survival after blunt chest trauma. Male C3H/HeN mice (n = 10 per group) were anesthetized and subjected to chest trauma or sham procedure. The cytokine release of cultured peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages and plasma levels of tumor necrosis factor-alpha and interleukin-6 from those animals were quantified. Sepsis was induced via cecal ligation and puncture 24 hrs after lung contusion. Two hours after blunt chest trauma, plasma tumor necrosis factor-alpha and interleukin-6 were markedly increased, as was peripheral blood mononuclear cell cytokine production, lung myeloperoxidase activity, and lung chemokine concentrations. At 24 hrs and, in part, already at 2 hrs, cytokine release from peritoneal macrophages, splenic macrophages, and splenocytes was significantly suppressed. Furthermore, pulmonary contusion when followed by moderate sepsis significantly diminished survival rate when compared with chest trauma or moderate sepsis alone. These results indicate that pulmonary contusion causes severe immunodysfunction of splenocytes, macrophages, and monocytes in different local compartments and systemically. Moreover, this immunosuppression is associated with an increased susceptibility to infectious complications, which results in a decreased survival rate if blunt chest trauma is followed by a septic insult.

Blunt chest trauma induces delayed splenic immunosuppression.

Severe blunt chest trauma is frequently associated with multiple organ failure and sepsis. Posttraumatic immunosuppression seems to play a major role in their development. However, the immunologic alterations following pulmonary contusion are insufficiently elucidated. Specifically, it remains unknown whether immunocompetent cells located distant from the site of the impact are affected. We therefore aimed to characterize the influence of pulmonary contusion on lymphocytes and splenic macrophages. Male C3H/HeN mice (n = 8-10/group) were anesthetized and subjected to trauma or sham procedure. Blunt chest trauma was induced by a blast wave focused on the thorax. Two or 24 h later, splenocytes and splenic macrophages were isolated and stimulated for 48 h. The cytokine release (IFN-gamma, IL-2, IL-3, IL-10, IL-12, IL-18) from splenocytes as well as from splenic macrophages (TNF-alpha, IL-10, IL-12, IL-18) and plasma levels of TNF-alpha and IL-6 were quantified by ELISA. The results indicate that at 2 h after blunt chest trauma, plasma TNF-alpha and IL-6 were markedly increased. At the same time, no differences in splenocyte cytokine production were detectable. However, at 24 h a significantly depressed cytokine release was observed in trauma animals. Furthermore, splenic macrophages showed a significantly decreased production of TNF-alpha, IL-10, and IL-12 at 24 h and markedly increased release of IL-18 at 2 h after trauma. These results indicate that blunt chest trauma causes severe immunodysfunction of lymphocytes and splenic macrophages. Thus, lung contusion as a localized type of trauma causes dysfunction of immunocompetent cell populations, which are located distant from the site of injury.

Lymphocyte function in wound healing and following injury.

Injury activates a cascade of local and systemic immune responses. A literature review was undertaken of lymphocyte function in wound healing and following injury. Lymphocytes are not required for the initiation of wound healing, but an intact cellular immune response is essential for a normal outcome of tissue repair. Injury affects lymphocyte immune mechanisms leading to generalized immunosuppression which, in turn, increases host susceptibility to infection and sepsis. Although the exact origin of post-traumatic immunosuppression remains unknown, stress hormones and immunosuppressive factors, such as inflammatory cytokines, prostaglandin E2 and nitric oxide, affect lymphocyte function adversely. Post-traumatic impairment of T lymphocyte immune function is reflected in decreased lymphocyte numbers, as well as altered T cell phenotype and activity. Antibody-producing B lymphocytes are variably affected by injury, probably secondary to alterations of T lymphocyte function, as a result of their close interaction with helper T cells. Therapeutic modulation of the host immune response may include non-specific and specific interventions to improve overall defence mechanisms. Early resuscitation to restore lymphocyte function after injury is important for tissue repair and the prevention of immunosuppression.

Gender-related outcomes in trauma.

Recent data suggest that sex hormones may play a role in regulating posttraumatic immunosuppression, leading to gender-based differences in outcome after injuries. This study examined gender-related outcomes in trauma patients. We conducted a retrospective review of trauma registry data from our Level I trauma center over a 4-year period. Patients > 15 years of age, with Injury Severity Scores > 15, who survived and received mechanical ventilation for > 48 hours were included. Patients were divided into two groups on the basis of age (15-45 years and > 45 years) and the groups were further stratified by gender. Groups were matched by Injury Severity Scores, Glasgow Coma Scale score, Abbreviated Injury Score for the head, and transfusion requirement. Gender-based outcomes consisted of ventilator days, intensive care unit length of stay (LOS), hospital LOS, pneumonia, and death. Data were reported as mean +/- SD. There were 612 patients. In the younger age group, male patients had a higher incidence of multiple organ failure (10.5% vs. 1.5%), longer intensive care unit (13.5 +/- 9.2 days vs. 9.2 +/- 7.2 days) and hospital LOS (30.2 +/- 37.7 days vs. 18.9 +/- 13.0 days), and higher mortality (13.4% vs. 6.8%) compared with female patients (p < 0.05 for all). These differences did not exist in the older age group. The incidence of pneumonia did not differ by gender. Age > 45 years was associated with higher mortality (odds ratio, 2.0; 95% confidence interval, 1.1-3.5). Although the incidence of pneumonia was not influenced by gender, female trauma patients had better outcomes than male patients in the younger age group. Outcome in the older age group was not gender-related. Our data support a gender-based difference in outcome after traumatic injuries in younger patients.

Postinjury Malaria: A Study of Trauma Victims in Cambodia

The pattern of host defense against plasmodium is comparable to the immune response to bacterial infection. Posttraumatic immunosuppression may therefore cause relapses of malaria secondary to trauma and trauma surgery in asymptomatic carriers of the parasites in endemic areas. To our knowledge this has not been validated in epidemiologic studies. Postinjury malaria was registered retrospectively in 342 land mine and war victims from malaria-endemic areas in Cambodia. The incidence rate was analyzed in terms of age, gender, preinjury endemicity, evacuation times, anatomic injury severity, systolic blood pressure at admission, blood transfusion, and duration of the first surgical intervention as independent variables. The rate of postinjury malaria in the study patients was 33.3% (95% CI, 28.3-38.3%). Injury Severity Score (ISS) and surgical operation time were risk factors (area under the curve in receiver operating characteristic plots were 0.73 and 0.79, respectively). The impact of the other risk factors was nonsignificant. Despite difficulties in diagnosing postoperative malaria in endemic areas, the study demonstrates that the rate of postinjury malaria is high. The results legitimate controlled trials of immediate postinjury chemoprophylaxis to severely injured in endemic areas. The authors recommend staged surgical operations with brief primary interventions in victims with severe injuries.