Age-related immune responses after burn and inhalation injury are associated with altered clinical outcomes.
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ABSTRACT:
SUBMITTER: Frankel JH
PROVIDER: S-EPMC5871535 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
Age-related immune responses after burn and inhalation injury are associated with altered clinical outcomes.
Frankel John H JH Boe Devin M DM Albright Joslyn M JM O'Halloran Eileen B EB Carter Stewart R SR Davis Christopher S CS Ramirez Luis L Burnham Ellen L EL Gamelli Richard L RL Afshar Majid M Kovacs Elizabeth J EJ
Experimental gerontology 20171026
This prospective study aimed to address changes in inflammatory response between different aged populations of patients who sustained burn and inhalation injury. Plasma and bronchoalveolar lavage (BAL) samples were collected from 104 patients within 15h of their estimated time of burn injury. Clinical variables, laboratory parameters, and immune mediator profiles were examined in association with clinical outcomes. Older patients were at higher odds for death after burn injury (odds ratio (OR)=7 ...[more]
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Project description:BackgroundIn the patient with burn injury, older age, larger percentage of total body surface area (TBS) burned, and inhalation injury are established risk factors for death, which typically results from multisystem organ failure and sepsis, implicating burn-induced immune dysregulation as a contributory mechanism. We sought to identify early transcriptomic changes in circulating leukocytes underlying increased mortality associated with these three risk factors.MethodsWe performed a retrospective analysis of the Glue Grant database. From 2003 to 2010, 324 adults with 20% or greater TBS burned were prospectively enrolled at five US burn centers, and 112 provided blood samples within 1 week after burn. RNA was extracted from pooled leukocytes for hybridization onto Affymetrix HU133 Plus 2.0 GeneChips. A multivariate regression model was constructed to determine risk factors for mortality. Testing for differential gene association associated with age, burn size, and inhalation injury was based on linear models using a fold change threshold of 1.5 and false discovery rate of 0.05.ResultsAfter adjusting for potential confounders, age greater than 60 years (relative risk [RR], 4.53; 95% confidence interval [CI], 2.93-6.99), burn size greater than 40% TBS (RR, 4.24; 95% CI, 2.61-6.91), and inhalation injury (RR, 2.08; 95% CI, 1.35-3.21) were independently associated with mortality. No genes were differentially expressed in association with age greater than 60 years or inhalation injury. Fifty-one probe sets representing 39 unique genes were differentially expressed in leukocytes from patients with burn size greater than 40% TBS; these genes were associated with platelet activation and degranulation/exocytosis, and gene-set enrichment analysis suggested increased cellular proliferation and down-regulation of proinflammatory cytokines.ConclusionAmong adults with large burns, older age, increasing burn size, and inhalation injury have a modest effect on the leukocyte transcriptome in the context of the "genomic storm" induced by a 20% or greater than TBS burned. The 39-gene signature we identified may provide novel targets for the development of therapies to reduce morbidity and mortality associated with burns greater than 40% TBS.Level of evidenceEpidemiologic study, level III.
| S-EPMC4731271 | biostudies-literature
Project description:Modulating immune responses to sepsis and trauma remain one of the most difficult challenges in modern medicine. Large burn injuries (LBI) are a severe form of trauma associated with sepsis, immune impairment, and mortality. Immune dysfunction after LBI is complex, involving both enhanced and impaired immune activation. The release of Damage-Associated Molecular Patterns (DAMPs), such as HMGB1, and cytokines (e.g. IL-1β) creates an environment of immune dysfunction often leading to end organ failure and death. Both HMGB1 and IL-1β have been found to play critical roles in sepsis and post-burn immune dysfunction. HMGB1 and IL-1β have been shown previously to form potent complexes in vitro. We recently identified the presence of HMGB1/IL-1β heterocomplexes in human tissue. We now find HMGB1/IL-1β complexes in human and mouse plasma, and identify a synergistic role of HMGB1/IL-1β complexes in post-burn immune dysfunction. In both humans and mice, we found that HMGB1 was enriched in plasma microvesicles (MVs) after LBI. HMGB1 was found form complexes with IL-1β. Using flow cytometry of mouse plasma MVs, we identified an increase in an HMGB1+/IL-1β+ MVs. Using co-IP, HMGB1 was found to bind the pro-form of IL-1β in mouse and human plasma. Pro-IL-1β, which is traditionally considered inactive, became active when complexed with HMGB1. Human THP-1 monocytes treated with HMGB1-pro-IL-1β complexes showed increased transcription of LBI associated cytokines IL-6 and IFNβ along with suppression of iNOS, mimicking findings associated with LBI. These findings identify that HMGB1/IL-1β complexes released after burn injuries can modulate immune responses, and microvesicles are identified as a novel reservoir for these immune mediators. These complexes might serve as novel immune targets for the treatment of systemic immune responses due to LBI or other causes of sepsis.
| S-EPMC5877880 | biostudies-literature
Project description:Recovery from burn injury is associated with stimulated whole-body protein turnover. Since skeletal muscle and liver are the tissues most likely to influence whole-body measurements, we studied protein kinetics in soleus and plantaris muscles as well as liver 3 days after a 3 s burn on one hindlimb of the rat. Muscles from both the burned and unburned limbs of burned rats were compared with those of uninjured controls to distinguish between local and systemic factors involved. The following measurements were performed: (1) fractional growth rate of the tissue protein pool, determined from tissue protein content on days 2, 3 and 4; (2) fractional protein-synthetic rate, measured by [14C]tyrosine constant infusion on day 3; (3) fractional protein-degradation rate, calculated from the difference between the rates of protein synthesis and growth. Protein growth by soleus and plantaris muscles of control rats and unburned limb of burned rats was not paralleled by those in the burned limb, which showed progressive atrophy between 2 and 4 days post-burn (P less than 0.005). Protein synthesis by soleus but not plantaris muscle in the unburned limb of burned rats was enhanced by 62% (P less than 0.04) above control. Protein synthesis by burned-limb soleus and plantaris muscles was elevated by 114% (P less than 0.001) and 67% (P less than 0.02) respectively above control. Protein degradation by both soleus and plantaris muscles in the unburned limb of burned rats did not differ from control. In contrast, that of soleus and plantaris muscles in the burned limb was stimulated by 230% (P less than 0.001) and 164% (P less than 0.001) respectively compared with controls. Protein turnover of soleus muscles in both control and burned rats was more rapid than in corresponding plantaris muscles. Liver protein mass exhibited steady growth in control rats, but remained unchanged in burned animals between 2 and 4 days post-burn. Liver protein synthesis in burned rats was elevated by 56% (P less than 0.01) and protein breakdown was stimulated by 61% (P less than 0.002) above those of controls. The data indicate that both local and systemic factors influence tissue protein turnover in animals recovering from a single-hindlimb scald.
| S-EPMC1144358 | biostudies-other
Project description:BackgroundSystemic inflammatory response syndrome (SIRS) is associated with organ failure and infectious complications after major burn injury. Recent evidence has linked melanocortin signaling to anti-inflammatory and wound-repair functions, with mutations in the melanocortin 1 receptor (MC1R) gene leading to increased inflammatory responses. Our group has previously demonstrated that MC1R gene polymorphisms are associated with postburn hypertrophic scarring. Thus, we hypothesized that MC1R single nucleotide polymorphisms (SNPs) would be associated with increased burn-induced SIRS and increased infectious complications.MethodsWe performed a retrospective cohort study of adults (>18 y of age) admitted to our burn center with >20% total body surface area (TBSA) partial/full thickness burns between 2006 and 2013. We screened for five MC1R SNPs (V60L, V92M, R151C, R163Q, T314T) by polymerase chain reaction from genomic DNA isolated from blood samples. We performed a detailed review of each patient chart to identify age, sex, race, ethnicity, %TBSA burned, burn wound infections (BWIs), and 72-hr intravenous fluid volume, the latter a surrogate for a dysfunctional inflammatory response to injury. Association testing was based on multivariable regression.ResultsOf 106 subjects enrolled, 82 had complete data for analysis. Of these, 64 (78%) were male, with a median age of 39 and median burn size of 30% TBSA. A total of 36 (44%) subjects developed BWIs. The median total administered IV crystalloid in first 72h was 24.6 L. In multivariate analysis, the R151C variant allele was a significant independent risk factor for BWI (adjusted prevalence ratio 2.03; 95% CI: 1.21-3.39; P = 0.007), and the V60L variant allele was independently associated with increased resuscitation fluid volume (P = 0.021).ConclusionsThis is the first study to demonstrate a significant association between genetic polymorphisms and a nonfatal burn-induced SIRS complication. Our findings suggest that MC1R polymorphisms contribute to dysfunctional responses to burn injury that may predict infectious and inflammatory complications.
| S-EPMC6464811 | biostudies-literature
Project description:BackgroundSmoke inhalation injury increases overall burn mortality. Locally applied heparin attenuates lung injury in burn animal models of smoke inhalation. It is uncertain whether local treatment of heparin is benefit for burn patients with inhalation trauma. We systematically reviewed published clinical trial data to evaluate the effectiveness of nebulized heparin in treating burn patients with inhalation injury.MethodsA systematic search was undertaken in PubMed, the Cochrane Library, Embase, Web of Science, the Chinese Journals Full-text Database, the China Biomedical Literature Database and the Wanfang Database to obtain clinical controlled trails evaluating nebulized heparin in the treatment of burn patients with inhalation injury. Patient and clinical characteristics, interventions and physiological and clinical outcomes were recorded. Cochrane Risk of Bias Evaluation Tool and the Newcastle-Ottawa Scale were used to evaluate data quality. Potential publication bias was assessed by Egger's test. A sensitivity analysis was conducted to assess the stability of the results. The meta-analysis was conducted in R 3.5.1 software.ResultsNine trials were eligible for the systematic review and meta-analysis. Nebulized heparin can reduce lung injury and improve lung function in burn patients with inhalation injury without abnormal coagulation or bleeding, but the findings are still controversial. Mortality in the heparin-treated group was lower than that of the traditional treatment group (relative risk (RR) 0.75). The duration of mechanical ventilation (DOMV) was shorter in the heparin-treated group compared to the traditional treatment group (standardized mean difference (SMD) -0.78). Length of hospital stay was significantly shorter than that in the traditional treatment group (SMD -0.42), but incidence rates of pneumonia and unplanned reintubation were not significantly different in the study groups (RRs 0.97 and 0.88, respectively). No statistically significant publication biases were detected for the above clinical endpoints (p?>?0.05).ConclusionsBased on conventional aerosol therapy, heparin nebulization can further reduce lung injury, improve lung function, shorten DOMV and length of hospital stay, and reduce mortality, although it does not reduce the incidence of pneumonia and/or the unplanned reintubation rate.
| S-EPMC7271764 | biostudies-literature
Project description:Spinal cord injury (SCI) causes lifelong debilitating conditions. Previous works demonstrated the essential role of the immune system in recovery after SCI. Here, we explored the temporal changes of the response after SCI in young and aged mice in order to characterize multiple immune populations within the mammalian spinal cord. We revealed substantial infiltration of myeloid cells to the spinal cord in young animals, accompanied by changes in the activation state of microglia. In contrast, both processes were blunted in aged mice. Interestingly, we discovered the formation of meningeal lymphatic structures above the lesion site, and their role has not been examined after contusive injury. Our transcriptomic data predicted lymphangiogenic signaling between myeloid cells in the spinal cord and lymphatic endothelial cells (LECs) in the meninges after SCI. Together, our findings delineate how aging affects the immune response following SCI and highlight the participation of the spinal cord meninges in supporting vascular repair.
| S-EPMC10523880 | biostudies-literature
Project description:Burn injury destroys skin, the second largest innate immune organ in the body, and triggers chaotic immune and inflammatory responses. The pattern recognition molecule, mannan-binding lectin (MBL), plays an important role in the first-line host defense against infectious agents. MBL initiates the lectin complement pathway and acts as an opsonin. Recent studies suggest that MBL also modulates inflammatory responses. We report that local responses after burn in MBL null mice differ from those found in wild-type (WT) mice in the following important biological markers: spontaneous eschar separation, thinned epidermis and dermis, upregulation of soluble factors including cytokines, chemokines, cell adhesion molecules, a growth factor-binding protein, and matrix metalloproteinases. Mice lacking C1q, C4, or C3 did not show the lack of eschar separation seen in MBL null-burn phenotype. These findings implicate MBL as an important molecule in the maintenance of the homeostatic balance.
| S-EPMC2936508 | biostudies-literature
Project description:Current studies of particulate matter (PM) are confounded by the fact that PM is a complex mixture of primary (crustal material, soot, metals) and secondary (nitrates, sulfates, and organics formed in the atmosphere) compounds with considerable variance in composition by sources and location. We have developed a laboratory-based PM that is replicable, does not contain dust or metals and that can be used to study specific health effects of PM composition in animal models. We exposed both neonatal (7 days of age) and adult rats to a single 6-h exposure of laboratory generated fine diffusion flame particles (DFP; 170 µg/m(3)), or filtered air. Pulmonary gene and protein expression as well as indicators of cytotoxicity were evaluated 24 h after exposure. Although DFP exposure did not alter airway epithelial cell composition in either neonates or adults, increased lactate dehydrogenase activity was found in the bronchoalveolar lavage fluid of neonates indicating an age-specific increase in susceptibility. In adults, 16 genes were differentially expressed as a result of DFP exposure whereas only 6 genes were altered in the airways of neonates. Glutamate cysteine ligase protein was increased in abundance in both DFP exposed neonates and adults indicating an initiation of antioxidant responses involving the synthesis of glutathione. DFP significantly decreased catalase gene expression in adult airways, although catalase protein expression was increased by DFP in both neonates and adults. We conclude that key airway antioxidant enzymes undergo changes in expression in response to a moderate PM exposure that does not cause frank epithelial injury and that neonates have a different response pattern than adults.
| S-EPMC3111018 | biostudies-literature
Project description:BackgroundInjury to the airways after smoke inhalation is a major mortality risk factor in victims of burn injuries, resulting in a 15-45% increase in patient deaths. Damage to the airways by smoke may induce acute respiratory distress syndrome (ARDS), which is partly characterized by hypoxemia in the airways. While ARDS has been associated with bacterial infection, the impact of hypoxemia on airway microbiota is unknown. Our objective was to identify differences in microbiota within the airways of burn patients who develop hypoxemia early after inhalation injury and those that do not using next-generation sequencing of bacterial 16S rRNA genes.ResultsDNA was extracted from therapeutic bronchial washings of 48 patients performed within 72 hours of hospitalization for burn and inhalation injury at the North Carolina Jaycee Burn Center. DNA was prepared for sequencing using a novel molecule tagging method and sequenced on the Illumina MiSeq platform. Bacterial species were identified using the MTToolbox pipeline. Patients with hypoxemia, as indicated by a PaO2/FiO2 ratio ≤ 300, had a 30% increase in abundance of Streptococcaceae and Enterobacteriaceae and 84% increase in Staphylococcaceae as compared to patients with a PaO2/FiO2 ratio > 300. Wilcoxon rank-sum test identified significant enrichment in abundance of OTUs identified as Prevotella melaninogenica (p = 0.042), Corynebacterium (p = 0.037) and Mogibacterium (p = 0.048). Linear discriminant effect size analysis (LefSe) confirmed significant enrichment of Prevotella melaninognica among patients with a PaO2/FiO2 ratio ≤ 300 (p<0.05). These results could not be explained by differences in antibiotic treatment.ConclusionsThe airway microbiota following burn and inhalation injury is altered in patients with a PaO2/FiO2 ratio ≤ 300 early after injury. Enrichment of specific taxa in patients with a PaO2/FiO2 ratio ≤ 300 may indicate airway environment and patient changes that favor these microbes. Longitudinal studies are necessary to identify stably colonizing taxa that play roles in hypoxemia and ARDS pathogenesis.
| S-EPMC5373524 | biostudies-literature
Project description:Pulmonary and systemic insults from inhalation injury can complicate the care of burn patients and contribute to significant morbidity and mortality. However, recent progress in diagnosis and treatment of inhalation injury has not kept pace with the care of cutaneous thermal injury. There are many challenges unique to inhalation injury that have slowed advancement, including deficiencies in our understanding of its pathophysiology, the relative difficulty and subjectivity of bronchoscopic diagnosis, the lack of diagnostic biomarkers, the necessarily urgent manner in which decisions are made about intubation, and the lack of universal recommendations for the application of mucolytics, anticoagulants, bronchodilators, modified ventilator strategies, and other measures. This review represents a summary of critical shortcomings in our understanding and management of inhalation injury identified by the American Burn Association's working group on Cutaneous Thermal Injury and Inhalation Injury in 2018. It addresses our current understanding of the diagnosis, pathophysiology, and treatment of inhalation injury and highlights topics in need of additional research, including 1) airway repair mechanisms; 2) the airway microbiome in health and after injury; and 3) candidate biomarkers of inhalation injury.
| S-EPMC6939826 | biostudies-literature