Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

Ageing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-alpha) initiates the inflammatory cascade and has been linked to several age-associated disorders. It remains, however, unknown if TNF-alpha is associated with mortality in old populations. The aim of the present study was to investigate if serum levels of TNF-alpha were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF-alpha and IL-6 on survival in the following 6 years. A total of 133 participants died during this follow-up period. TNF-alpha was associated with mortality in men, but not in women, whereas low-grade elevations in IL-6 were associated strongly with mortality in both sexes. TNF-alpha explained only 7% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate that at least in old populations chronic elevated levels of TNF-alpha and IL-6 have different biological functions that trigger age-associated pathology and cause mortality.     

Genetic priming of a proinflammatory profile predicts low IQ in octogenarians

The purpose of the study was to test the hypothesis that single nucleotide polymorphisms (SNPs) within interleukin (IL)-18, TNF-alpha, IL-6 and IL-10 gene promoter regions are risk factors for cognitive decline in healthy octogenarians, and to isolate the strongest inflammatory biomarkers of cognitive function in the peripheral blood. The Wechsler Adult Intelligence Scale was administered to 112 individuals at ages 80 and 85. An IL-18 haplotype was an independent risk factor of poor Performance IQ. The TNF-308GA genotype was related to individual declines in Verbal IQ, and the IL-10-592 CC genotype was related to better Verbal IQ at the age of 80. Circulating levels of TNF-alpha, sTNFRs, and IL-6 were negatively correlated with IQ at age 85 and less strongly to IQ at age 80 with activation of the TNF system as the strongest biomarker. In conclusion, SNPs related to high proinflammatory or low anti-inflammatory activity are independent risk factors of reduced cognitive function in octogenarians. Only the IL-18 haplotype was associated with inflammation in the peripheral blood and only with regard to circulating TNF-alpha.     

Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease

Multiple pathogenic factors may contribute to the pathophysiology of Alzheimer's disease (AD). Peripheral markers have been used to assess biochemical alterations associated with AD and mild cognitive impairment (MCI) involved in its pathophysiology. The present study was conducted to evaluate inflammatory peripheral markers in elderly patients with MCI, patients with AD and normal elderly subjects. We measured plasma levels of different cytokines (IL-6, TNF-alpha and IFN-alpha) and platelet levels of cyclooxigenase-2 (COX-2) from 34 patients with MCI, 45 patients with AD and 28 age-matched control subjects. MCI and AD patients showed similarities in TNF-alpha and COX-2 levels, and differences in IL-6 and INF-alpha. Whereas augmented IL-6 levels have been found in AD patients, a significant increase in INF-alpha has been detected only in patients with MCI possibly associated with the depression stage frequently found in cognitive impairment. In conclusion, inflammatory response may be an early factor in AD development and these changes in circulating markers are possibly related to the progression of MCI to AD.     

The inflammatory response to vaccination is altered in the elderly

To further explore whether immune function and acute phase response are altered during ageing, the response to a mild inflammatory stress (DT-Polio-Typhim vaccination) was studied in elderly and young subjects. Cytokine production (IFN-gamma, TNF-alpha, IL-6, IL-10) by whole blood cultures, circulating cytokines and acute phase proteins were analysed before and 2 days after vaccination. Prior to vaccination, only IFN-gamma production was lower in the elderly than in the young subjects due to a lower mononuclear cell number. In the same time, although in the normal range, several acute phase proteins were greater in elderly than in young subjects, suggesting a low-grade inflammatory state in the elderly. After vaccination, IFN-gamma production remained lower in the elderly than in the young, supporting an altered cell-mediated immunity with advancing age. TNF-alpha production was unaffected by either ageing or vaccination. IL-6 production was stimulated by vaccination in young subjects but not significantly in the elderly. IL-10 production was inhibited by vaccination in the elderly but not in the young. Acute phase proteins were less increased in elderly than in young subjects. Taken together, these results support a general lack of inflammatory response in the elderly exposed to an immune challenge and suggest that immune deficiency may concern both Th1 and Th2 responses. However, the interpretation must respect the limitation of small subjects number.     

Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans.

Ageing is associated with decreased resistance to bacterial infections and concomitant increased circulating levels of inflammatory cytokines. The purpose of the present study was to research age-related changes in levels of early mediators of the acute-phase response in whole blood supernatants following LPS stimulation, representing an ex vivo model of sepsis. Levels of tumour necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 in whole blood supernatants were measured after in vitro LPS stimulation for 24 h in 168 elderly humans aged 81 years from the 1914 cohort in Glostrup, Denmark and in 91 young controls aged 19-31 years. Levels of TNF-alpha and IL-1beta were significantly lower in elderly humans compared with young controls, whereas no difference was detected with regard to IL-6. Elderly humans with low body mass index had the lowest levels of IL-1beta. Young women had lower levels of proinflammatory cytokines compared with young men, but this difference was blurred by ageing. No relation was found between circulating plasma levels of TNF-alpha and levels after in vitro LPS stimulation. In conclusion, decreased production of TNF-alpha and IL-1beta after exposure to LPS may reflect impaired host defence against infections in the elderly and be of importance in elderly humans with underlying health disorders. However, the clinical relevance is questionable in healthy elderly people because decreased levels were found compared with young men but not compared with young women.     

Common studied polymorphisms do not affect plasma cytokine levels upon endotoxin exposure in humans

The aim of this study was to investigate to what extent single nucleotide polymorphisms (SNPs) in promoter regions of genes of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF)-alpha, interleukin (IL)-18, interferon (IFN)-gamma, IL-6 and IL-10 affect the cytokine response during a controlled low-grade inflammatory response in vivo. Two hundred healthy young male volunteers were genotyped, and cytokine levels were measured in response to a low-dose intravenous bolus of Escherichia coli endotoxin. No association was detected between SNPs (TLR-4299, TLR-4399, TNF-308, IL-18-137, IL-18-607, IFN-gamma+874, IL-6-174, IL-10-592 and IL-10-1082) and endotoxin-induced changes in plasma levels of TNF-alpha, IL-6 and IL-10. IL-18 levels were unaffected by endotoxin. In conclusion, the investigated SNPs did not affect endotoxin-induced low-grade cytokine production of TNF-alpha, IL-6, IL-18 or IL-10 in healthy young men. Previous reports of a major heritability factor in the inflammatory response may be due to other target genes or effects in older age groups or women.     

Circulating inflammatory mediators predict shock and mortality in febrile patients with microbial infection

The host response to microbial infection is associated with the release of inflammatory mediators. We hypothesized that the type and degree of the systemic response as reflected by levels of circulating mediators predict morbidity and mortality, according to the invasiveness of microbial infection. We prospectively studied 133 medical patients with fever and culture-proven microbial infection. For 3 days after inclusion, the circulating levels of activated complement C3a, interleukin (IL)-6, and secretory phospholipase A(2) (sPLA(2)) were determined daily. Based on results of microbiological studies performed for up to 7 days, patients were classified as having local infections (Group 1, n = 80 positive local cultures or specific stains for fungal or tuberculous infections) or bacteremia (Group 2, n = 52 plus 1 patient with malaria parasitemia). Outcome was assessed as the development of septic shock and as mortality up to 28 days after inclusion. Fifteen patients (11%) developed septic shock and overall mortality was 18% (n = 24). Bacteremia was associated with shock and shock predisposed to death. Circulating mediator levels were generally higher in Group 2 than in Group 1. Circulating levels of IL-6 and sPLA(2) were higher in patients developing septic shock and in nonsurvivors, particularly in Group 1. High C3a was particularly associated with nonsurvival in Group 2. In Group 1, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the peak sPLA(2) for shock development was 0.79 (P < 0.05). The AUC of the ROC curve of the peak IL-6 and sPLA(2) for mortality was 0.69 and 0.68 (P < 0.05), respectively. In Group 2, the AUC of the ROC for peak C3a predicting mortality was 0.73 (P < 0.05). In conclusion, in medical patients with fever and microbial infection, the systemic inflammatory host response predicts shock and death, at an early stage, dependent on the invasiveness of microbial infection. The results suggest a differential pathogenetic role of complement activation on the one hand and release of cytokine and lipid mediators on the other in bacteremic and local microbial infections, respectively. They may partly explain the failure of strategies blocking proinflammatory cytokines or sPLA(2) in human sepsis and may extend the basis for attempts to inhibit complement activation at an early stage in patients at risk of dying from invasive microbial infections.     

Circulating Heat Shock Protein 70 in Health,Aging and Disease

Background

Heat shock proteins (Hsp) are ubiquitously synthesised in virtually all species and it is hypothesised that they might have beneficial health effects. Recent studies have identified circulating Hsp as an important mediator in inflammation - the effects of low-grade inflammation in the aging process are overwhelming. While much is known about intracellular Hsp70, scant data exist on circulating Hsp70 in the aging context. Therefore, the objectives of this study were to investigate the effect of age and disease on circulating Hsp70 and, in particular, to evaluate the association between circulating Hsp70 and inflammatory parameters.

Results

Serum Hsp70, Interleukin (IL) -10, IL-6 and Tumor Necrosis Factor (TNF) alpha concentrations were determined in 90 hospitalised geriatric patients (aged 83 ± 6 years) and in 200 community-dwelling control subjects (100 elderly, aged 74 ± 5 years, and 100 young, aged 23 ± 3 years). In the community-dwelling elderly, serum Hsp70 and IL-10 concentrations were significantly lower and IL-6 was significantly higher when compared to healthy young control subjects. Elderly patients presenting inflammation (CRP serum levels ≥5 mg/L) showed significantly (p = 0.007) higher Hsp70 values; and Hsp70 correlated positively (p < 0.001) with IL-6 and CRP, but not with TNF-alpha or IL-10. A significant association was also noted between Hsp70 levels and the degree of dependency and cognitive decline in geriatric patients.

Conclusions

The present data provide new evidence that serum concentration of Hsp70 decreases with age in a normal population. Our study also shows that higher levels of Hsp70 are associated with inflammation and frailty in elderly patients.

     

Frailty for predicting all-cause mortality in elderly acute coronary syndrome patients: A meta-analysis

BackgroundFrailty has been identified as a risk factor for mortality in patients with acute coronary syndrome (ACS). This meta-analysis aimed to evaluate the association between frailty and all-cause mortality outcome in patients with ACS.MethodsPubmed and Embase databases were searched up to September 26, 2018 for the observational studies evaluating the association between frailty and all-cause mortality in elderly ACS patients. Outcome measures were in-hospital death, short-term all-cause mortality (≤6 months),and long-term all-cause mortality (≥12 months).The impact of frailty on all-cause mortality was summarized as hazard ratios (HR) with 95% confidence intervals (CI) for the frail versus nonfrail patients.ResultsA total of 9 cohort studies involving 2475 elderly ACS patients were included. Meta-analysis showed that ACS patients with frailty had an increased risk of in-hospital death (HR 5.49; 95% CI 2.19–13.77), short-term all-cause mortality (HR 3.56; 95% CI 1.96–6.48), and long-term all-cause mortality (HR 2.44; 95% CI 1.92–3.12) after adjustment for confounding factors. In addition, prefrailty was also associated with an increased all-cause mortality (HR 1.65; 95% CI 1.01–2.69).ConclusionsThis meta-analysis demonstrates that frailty independently predicts all-cause mortality in elderly ACS patients. Elderly ACS patients should be assessed the frailty status for improving risk stratification.     

Antimonial therapy induces circulating proinflammatory cytokines in patients with cutaneous leishmaniasis

The objective of this study was to evaluate the association between antimonial therapy and circulating levels of proinflammatory cytokines in patients with cutaneous leishmaniasis (CL). Patients were treated with conventional chemotherapy by using pentavalent antimonium salts (Glucantime) for 3 weeks. Circulating plasma levels of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) were determined for CL patients and healthy subjects before and 3 weeks after the treatment was started. Plasma IL-1beta, IL-6, IL-8, and TNF-alpha levels were significantly higher for pretreatment CL patients than for healthy subjects. Proinflammatory cytokines significantly increased after 21 days postinfection compared to levels for the pretreatment patients. These increments were approximately 3-fold for IL-1beta and TNF-alpha levels, 10-fold for IL-6 levels, and 20-fold for IL-8 levels in patients with CL. Taken together these results indicate that circulating proinflammatory cytokine levels were increased in patients with CL as a consequence of host defense strategies, and antimonial therapy may induce these cytokines by affecting the macrophage or other components of the host defense system.     

Association between inflammatory markers and frailty in institutionalized older men

Objectives

To determine whether higher serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high sensitivity C-reactive protein (CRP) were associated with frailty in the older institutionalized men.

Participants

The study enrolled 386 residents from a veterans care home in northern Taiwan in 2007. All participants were men. Residents younger than 65 years or with acute illness were excluded.

Methods

Frailty status was determined based on the frailty phenotype (indicators include weight loss, exhaustion, and low grip strength, slow walking speed). Participants with 3 or more of the indicators were defined as frail, with 1 or 2 as intermediate frail, with no as non-frail. Serum IL-6, TNF-α, and hsCRP levels were measured using enzyme-linked immunosorbent assay and modeled as tertile for severely skewed distributions.

Results

The mean age of the participants was 81.5 ± 4.9 years. The percentages of frail were 33.2%, intermediate frail 59.1% and nonfrail 7.8%. Higher IL-6 level was positively associated with the frail status. Adjusting for age, body mass index, smoking status, and comorbid conditions, serum IL-6 showed significant trend across frailty categories (P = 0.03 [95% CI 1.40–5.24]). No significant associations of TNF-α, and CRP level with frailty were observed. An IL-6 level of 1.79 pg/mL had the optimal predictive value for frailty, with an area under the receiver operating characteristic (ROC) curve of 0.66 (P = 0.01 [95% CI 0.53–0.78]).

Conclusion

Higher serum levels of IL-6 were associated with frailty status in the older institutionalized men with multiple comorbidities.     

Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: Results from a meta-analysis and exploratory meta-regression analysis

Frailty is common and associated with poorer outcomes in the elderly, but its role as potential cardiovascular disease (CVD) risk factor requires clarification. We thus aimed to meta-analytically evaluate the evidence of frailty and pre-frailty as risk factors for CVD. Two reviewers selected all studies comparing data about CVD prevalence or incidence rates between frail/pre-frail vs. robust. The association between frailty status and CVD in cross-sectional studies was explored by calculating and pooling crude and adjusted odds ratios (ORs) ±95% confidence intervals (CIs); the data from longitudinal studies were pooled using the adjusted hazard ratios (HRs). Eighteen cohorts with a total of 31,343 participants were meta-analyzed. Using estimates from 10 cross-sectional cohorts, both frailty and pre-frailty were associated with higher odds of CVD than robust participants. Longitudinal data were obtained from 6 prospective cohort studies. After a median follow-up of 4.4 years, we identified an increased risk for faster onset of any-type CVD in the frail (HR = 1.70 [95%CI, 1.18–2.45]; I² = 66%) and pre-frail (HR = 1.23 [95%CI, 1.07–1.36]; I² = 67%) vs. robust groups. Similar results were apparent for time to CVD mortality in the frail and pre-frail groups. In conclusion, frailty and pre-frailty constitute addressable and independent risk factors for CVD in older adults.     

Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer's disease

Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and lipid peroxides are elevated and concentrations of endothelial nitric oxide (eNO) decreased in type 2 diabetes mellitus and Alzheimer's disease. This suggests that both these diseases are low-grade systemic inflammatory conditions and are closely associated with each other. Recent studies revealed that plasma and tissue concentrations of enzymes butyrylcholinesterase and acetylcholinesterase are elevated in type 2 diabetes and Alzheimer's disease. Acetylcholine has anti-inflammatory actions. Hence, elevated butyrylcholinesterase and acetylcholinesterase concentrations will lead to a decrease in the levels of acetylcholine that could trigger the onset of low-grade systemic inflammation seen in type 2 diabetes and Alzheimer's disease. In view of this, we propose that butyrylcholinesterase and acetylcholinesterase will not only serve as therapeutic targets but also may serve as markers to predict the development of type 2 diabetes mellitus and Alzheimer's disease.     

The effect of age on the systemic inflammatory response in patients with community-acquired pneumonia

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Increasing age has been associated with elevated circulating levels of pro-inflammatory mediators. We aimed to determine the impact of ageing on the systemic inflammatory response to CAP. In total 201 CAP patients were enrolled. Blood samples were obtained upon presentation, and on days 2, 3 and 5. For the current analysis patients ≤50 and ≥80 years were included. The Pneumonia Severity Index (PSI) score was calculated at presentation. The study encompassed 46 CAP patients aged ≤50 years (median 37 years) and 41 CAP patients aged ≥80 years (median 84 years). In both groups Streptococcus pneumoniae was the common causative microorganism. Whereas most young patients had a PSI score of I (54%), 98% of elderly patients had a PSI score ≥III (p <0.001). Four elderly patients died vs. none of the young patients (p 0.045). Older patients demonstrated lower serum C-reactive protein levels on admission and during the course of their hospitalization (p 0.001) in spite of more severe disease. Serum concentrations of pro-inflammatory (interleukin (IL)-6 and IL-8) and anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) did not differ between age groups, although admission IL-8 levels tended to be higher in elderly patients (p 0.05). Cytokine levels were positively correlated with PSI in young but not in elderly patients. These results suggest that elderly patients show an absolute (C-reactive protein) or relative (cytokines) reduction in their systemic inflammatory response on admission for CAP.     

Human models of low-grade inflammation: bolus versus continuous infusion of endotoxin

Systemic low-grade inflammation is recognized in an increasing number of chronic diseases. With the aim of establishing an experimental human in vivo model of systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (0.3 ng/kg of body weight) either as a bolus injection or as a 4-h continuous intravenous infusion, as well as after saline administration, in 10 healthy male subjects on three separate study days. Only bolus endotoxin caused an increase in heart rate, whereas a slight increase in rectal temperature was observed in both endotoxin groups. Tumor necrosis factor alpha (TNF-alpha), interleukin-6, and neutrophil responses were earlier and more pronounced in the bolus trial compared with the infusion trial results, whereas lymphocytes increased after endotoxin bolus injection as well as infusion without any difference between groups. Finally, endotoxin activated the hypothalamo-pituitary-adrenal axis slightly earlier in the bolus compared to the infusion trial. The continuous endotoxin infusion model may be more representative of human low-grade inflammation than the bolus injection model due to a less dynamic and more sustained increase in circulating levels of inflammatory mediators over time. In conclusion, low-dose endotoxin infusion elicits an inflammatory response, as assessed by a rise in TNF-alpha, and the responses are significantly different according to whether low-dose endotoxin is applied as a bolus injection or as a continuous infusion.     

Frailty as a predictor of adverse outcomes in hospitalized older adults: A systematic review and meta-analysis

Frailty syndrome is prevalent among hospitalized older adults as are the occurrence of adverse outcomes. This systematic review and meta-analysis investigated whether frailty in older adults at hospital admission predicts adverse outcomes. Manual (ProQuest, conferences annals and references) and electronic searches (PUBMED, EMBASE, Web of Science, Lilacs, CINAHL, PsycINFO and Google Scholar) were performed. We included prospective studies of hospitalized older adults. Primary outcomes were functional decline at hospital discharge and mortality after discharge. Other data were considered secondary outcomes. Methodological quality was evaluated by the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Twenty-eight papers were included, corresponding to 19 cohorts (5 cohorts for functional decline and 16 for mortality), with moderate to good methodological quality. Being frail [RR: 1.32 (95%CI: 1.04; 1.67)] and pre-frail [RR: 1.51 (95%CI: 1.05; 2.17)] are risk factors for functional decline compared with being nonfrail. Frail individuals had a relative risk for in-hospital mortality and mortality in medium- and long-term compared to nonfrail (in-hospital RR: 8.20, medium RR: 9.49 and long RR: 7.94) and pre-frail (in-hospital RR: 3.19, medium RR: 3.31 and long RR: 3.72). The overall mortality risk in frail individuals is 3.49 and 2.14 times compared to nonfrail and pre-frail, respectively. Length of hospital stay was higher for frail older adults (13.5 days) compared with pre-frail (10.5 days) and nonfrail (8.3 days). Therefore, being frail at hospital admission is a risk factor for in-hospital mortality, long hospital stay, functional decline at hospital discharge, and mortality in the medium- and long-term.     

Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14 monocytes in frail older adults

Frailty has been increasingly recognized as an important clinical syndrome in old age. The frailty syndrome is characterized by chronic inflammation, decreased functional and physiologic reserve, and increased vulnerability to stressors, leading to disability and mortality. However, molecular mechanisms that contribute to inflammation activation and regulation in frail older adults have not been investigated. To begin to address this, we conducted a pathway-specific gene array analysis of 367 inflammatory pathway genes by lipopolysaccharide (LPS)-challenged CD14⁺ monocytes from 32 community-dwelling frail and age-, race-, and sex-paired nonfrail older adults (mean age 83 years, range 72-94). The results showed that ex vivo LPS-challenge induced average 2.0-fold or higher upregulated expression of 116 genes in frail participants and 85 genes in paired nonfrail controls. In addition, frail participants had 2-fold or higher upregulation in LPS-induced expression of 7 stress-responsive genes than nonfrail controls with validation by quantitative real time RT-PCR. These findings suggest upregulated expression of specific stress-responsive genes in monocyte-mediated inflammatory pathway in the syndrome of frailty with potential mechanistic and interventional implications.     

Frailty in people living with HIV

The life expectancy of people living with HIV (PLHIV) has dramatically improved with effective and well-tolerated antiretroviral therapy. This presents a new challenge in caring for this patient population, with up to 28% of older PLHIV being identified as frail. Studies suggest that the prevalence of frailty is higher in PLHIV compared to the general population, and that the onset of frailty occurs at an earlier age. Frail individuals often present with multiple and non-specific health complaints, fluctuating disability, falls and delirium, and are at higher risk for multiple adverse outcomes, post-operative complications, poor responses to vaccination and functional decline. They tend to require longer hospital admissions, are more likely to require nursing home care, and are at greater risk of mortality. The degree of frailty can fluctuate over time. Limited evidence exists to support the reversal of frailty, but epidemiological evidence suggests that interventions to assess and manage co-morbidities, reducing risk factors such as smoking, increasing exercise and optimising BMI, and improving personal and community resources, are all likely to reduce the risk of frailty. Physicians who care for PLHIV need to recognise and manage frailty in this patient population. This includes an understanding of: when to intervene aggressively in the management of an older patient with a new HIV diagnosis to delay or prevent permanent debility and frailty; when to acknowledge that the patient has become frail; and the role of geriatric medicine in addressing the specific issues and needs of this patient, such as maximising functional ability, preventing falls, reducing social isolation and improving quality of life.     

Organ-specific inflammation following acute ethanol and burn injury

Clinical and experimental evidence demonstrates that ethanol exposure prior to injury alters local and systemic inflammatory responses, increasing morbidity and mortality. Moreover, the aberrant inflammatory responses can directly and indirectly lead to the poor prognosis after injury by altering leukocyte infiltration into the wound site and remote organs and by suppressing immunity leading to increased susceptibility to opportunistic infections. Recent studies from our laboratory have focused on inflammatory responses at the wound site and in other distal organs after exposure to acute ethanol and burn injury. This combined insult leads to increased mortality after dermal or intratracheal pseudomonas infection, relative to infected mice given ethanol or burn injury alone. The increased mortality in mice given ethanol and burn injury parallels elevated serum levels of proinflammatory cytokines, IL-6 and TNF-alpha, marked infiltration of leukocytes into the lung and gut, as well as immunosuppression at the sites of infection. Bacterial translocation from the gut is likely to be responsible, in part, for the aberrant accumulation of leukocytes in the lungs of ethanol-exposed, burn-injured mice. Additionally, other factors, such as expression of adhesion molecules, increased chemokine production, and leakiness of the vascular endothelium, may also be involved.