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1.
Sci Rep ; 11(1): 16555, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400718

RESUMO

Oxylipins modulate the behavior of immune cells in inflammation. Soluble epoxide hydrolase (sEH) converts anti-inflammatory epoxyeicosatrienoic acid (EET) to dihydroxyeicosatrienoic acid (DHET). An sEH-inhibitor, TPPU, has been demonstrated to ameliorate lipopolysaccharide (LPS)- and sepsis-induced inflammation via EETs. The immunomodulatory role of DHET is not well characterized. We hypothesized that TPPU dampens inflammation and that sEH-derived DHET alters neutrophil functionality in burn induced inflammation. Outbred mice were treated with vehicle, TPPU or 14,15-DHET and immediately subjected to either sham or dorsal scald 28% total body surface area burn injury. After 6 and 24 h, interleukin 6 (IL-6) serum levels and neutrophil activation were analyzed. For in vitro analyses, bone marrow derived neutrophil functionality and mRNA expression were examined. In vivo, 14,15-DHET and IL-6 serum concentrations were decreased after burn injury with TPPU administration. In vitro, 14,15-DHET impaired neutrophil chemotaxis, acidification, CXCR1/CXCR2 expression and reactive oxygen species (ROS) production, the latter independent from p38MAPK and PI3K signaling. We conclude that TPPU administration decreases DHET post-burn. Furthermore, DHET downregulates key neutrophil immune functions and mRNA expression. Altogether, these data reveal that TPPU not only increases anti-inflammatory and inflammation resolving EET levels, but also prevents potential impairment of neutrophils by DHET in trauma.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Anti-Inflamatórios/uso terapêutico , Queimaduras/tratamento farmacológico , Neutrófilos/imunologia , Compostos de Fenilureia/uso terapêutico , Piperidinas/uso terapêutico , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Queimaduras/imunologia , Queimaduras/metabolismo , Queimaduras/patologia , Citocinas/sangue , Epóxido Hidrolases/antagonistas & inibidores , Feminino , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/metabolismo , Neutrófilos/classificação , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/genética , Piperidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Quimiocinas/fisiologia , Explosão Respiratória/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/genética
2.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209943

RESUMO

Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a "hypermetabolic response", an inflammatory process that can be extensive and become uncontrolled, leading to a generalized catabolic state and delayed healing. Catabolism causes the upregulation of inflammatory cells and innate immune markers in various organs, which may lead to multiorgan failure and death. Burns activate immune cells and cytokine production regulated by damage-associated molecular patterns (DAMPs). Trauma has similar injury-related immune responses, whereby DAMPs are massively released in musculoskeletal injuries and elicit widespread systemic inflammation. Hemorrhagic shock is the main cause of death in trauma. It is hypovolemic, and the consequence of volume loss and the speed of blood loss manifest immediately after injury. In burns, the shock becomes evident within the first 24 h and is hypovolemic-distributive due to the severely compromised regulation of tissue perfusion and oxygen delivery caused by capillary leakage, whereby fluids shift from the intravascular to the interstitial space. In this review, we compare the pathophysiological responses to burns and trauma including their associated clinical patterns.


Assuntos
Alarminas/metabolismo , Queimaduras/imunologia , Choque Hemorrágico/imunologia , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Mitocôndrias/metabolismo
3.
Mol Immunol ; 136: 118-127, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34130152

RESUMO

Pseudomonas aeruginosa (PA) is one of the most dominant causes of nosocomial infections in burn patients. Increasing emergence of antibiotic-resistant strains highlights the need for novel antimicrobial agents. Flagellin, the main component protein of flagellum, is determined as the major antigen interacting with anti-P. aeruginosa IgY antibodies. The current study was aimed to evaluate the antibacterial potency of IgY antibodies raised against recombinant type A, and B flagellins. The immunogenicity and specificity of IgY antibodies were confirmed through indirect ELISA and western blot analysis, respectively. Anti-flagellin IgYs reduced the motility, biofilm formation and invasion potency of both strains. The cell surface hydrophobicity (CSH) of bacteria was increased upon IgY treatment, and in vitro opsonophagocytosis assay confirmed the high protective potency of specific antibodies via polymorphonuclear leukocyte (PMN)-augmented bacterial cell killing. The protective efficacy of IgYs was also studied in both acute pneumonia and burn wound murine models. Anti-flagellin B-IgY induced 100 % and 40 % protection against laboratory, and hospital strains in burn wound model, respectively. Protection in acute pneumonia against all strains was 100 %. Anti-flagellin A-IgY failed to protect mice in burn wound model, but provided 100 % protection against all strains in acute pneumonia challenge. In vitro, ex vivo and in vivo experiments confirmed the dose-dependent and non-type specific essence of anti-flagellin IgY antibodies, providing the benefit of covering all strain types in a dose dependent manner. Our findings provide evidence that anti-flagellin IgY antibodies qualify as novel economical therapeutic option against PA infection.


Assuntos
Queimaduras/microbiologia , Flagelina/imunologia , Imunoglobulinas/imunologia , Pneumonia/microbiologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/imunologia , Animais , Biofilmes/crescimento & desenvolvimento , Queimaduras/imunologia , Galinhas , Infecção Hospitalar/microbiologia , Modelos Animais de Doenças , Imunização Passiva , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Pneumonia/imunologia , Infecções por Pseudomonas/imunologia
4.
Front Immunol ; 12: 649285, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093537

RESUMO

Heterotopic ossification (HO) is one of the most intractable disorders following musculoskeletal injury and is characterized by the ectopic presence of bone tissue in the soft tissue leading to severe loss of function in the extremities. Recent studies have indicated that immune cell infiltration and inflammation are involved in aberrant bone formation. In this study, we found increased monocyte/macrophage and mast cell accumulation during early HO progression. Macrophage depletion by clodronate liposomes and mast cell stabilization by cromolyn sodium significantly impeded HO formation. Therefore, we proposed that the dietary phytochemical quercetin could also suppress immune cell recruitment and related inflammatory responses to prevent HO. As expected, quercetin inhibited the monocyte-to-macrophage transition, macrophage polarization, and mast cell activation in vitro in a dose-dependent manner. Using a murine burn/tenotomy model, we also demonstrated that quercetin attenuated inflammatory responses and HO in vivo. Furthermore, elevated SIRT1 and decreased acetylated NFκB p65 expression were responsible for the mechanism of quercetin, and the beneficial effects of quercetin were reversed by the SIRT1 antagonist EX527 and mimicked by the SIRT agonist SRT1720. The findings in this study suggest that targeting monocyte/macrophage and mast cell activities may represent an attractive approach for therapeutic intervention of HO and that quercetin may serve as a promising therapeutic candidate for the treatment of trauma-induced HO by modulating SIRT1/NFκB signaling.


Assuntos
Queimaduras/complicações , Ossificação Heterotópica/tratamento farmacológico , Quercetina/administração & dosagem , Traumatismos dos Tendões/complicações , Animais , Queimaduras/imunologia , Carbazóis/administração & dosagem , Células Cultivadas , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/imunologia , Ossificação Heterotópica/patologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Células THP-1 , Traumatismos dos Tendões/imunologia , Tendões/patologia , Tenotomia/efeitos adversos , Fator de Transcrição RelA/metabolismo , Microtomografia por Raio-X
5.
Biomed Res Int ; 2021: 8836243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124262

RESUMO

Severe burns are acute wounds caused by local heat exposure, resulting in life-threatening systemic effects and poor survival. However, the specific molecular mechanisms remain unclear. First, we downloaded gene expression data related to severe burns from the GEO database (GSE19743, GSE37069, and GSE77791). Then, a gene expression analysis was performed to identify differentially expressed genes (DEGs) and construct protein-protein interaction (PPI) network. The molecular mechanism was identified by enrichment analysis and Gene Set Enrichment Analysis. In addition, STEM software was used to screen for genes persistently expressed during response to severe burns, and receiver operating characteristic (ROC) curve was used to identify key DEGs. A total of 2631 upregulated and 3451 downregulated DEGs were identified. PPI network analysis clustered these DEGs into 13 modules. Importantly, module genes mostly related with immune responses and metabolism. In addition, we identified genes persistently altered during the response to severe burns corresponding to survival and death status. Among the genes with high area under the ROC curve in the PPI network gene, CCL5 and LCK were identified as key DEGs, which may affect the prognosis of burn patients. Gene set variation analysis showed that the immune response was inhibited and several types of immune cells were decreased, while the metabolic response was enhanced. The results showed that persistent gene expression changes occur in response to severe burns, which may underlie chronic alterations in physiological pathways. Identifying the key altered genes may reveal potential therapeutic targets for mitigating the effects of severe burns.


Assuntos
Queimaduras , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Mapas de Interação de Proteínas/imunologia , Transcriptoma/imunologia , Queimaduras/genética , Queimaduras/imunologia , Queimaduras/patologia , Biologia Computacional , Humanos , Índices de Gravidade do Trauma
6.
Infect Immun ; 89(10): e0009121, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34152806

RESUMO

Of the 486,000 burn injuries that required medical treatment in the United States in 2016, 40,000 people were hospitalized, with >3,000 fatalities. After burn injury, humans are at increased risk of sepsis and mortality from infections caused by Pseudomonas aeruginosa, an opportunistic pathogen. We hypothesize that systemic events were initiated from the burn that increased the host's susceptibility to P. aeruginosa. A nonlethal 10% total body surface area (TBSA), full-thickness flame burn was performed in CD-1 mice without and with subsequent P. aeruginosa (strain M2) infection. The 50% lethal dose for subcutaneous infection with P. aeruginosa M2 at the burn site immediately after the burn decreased by 6 log, with mortality occurring between 18 and 26 h, compared with P. aeruginosa-infected mice without burn injury. Bacteria in distal organs were detected by 18 h, concurrent with the onset of clinical symptoms. Serum proinflammatory cytokines (interleukin-6 [IL-6], IL-1ß, gamma interferon, and tumor necrosis factor alpha) and the anti-inflammatory cytokine IL-10 were first detected at 12 h postburn with infection and continued to increase until death. Directly after burn alone, serum levels of HMGB1, a danger-associated molecular pattern and TLR4 agonist, transiently increased to 50 ng/ml before returning to 20 ng/ml. Burn with P. aeruginosa infection increased serum HMGB1 concentrations >10-fold (250 ng/ml) at the time of death. This HMGB1-rich serum stimulated TLR4-mediated NF-κB activation in a TLR4 reporter cell line. Treatment of infected burned mice with P5779, a peptide inhibitor of HMGB1, increased the mean survival from 23 to 42 h (P < 0.0001). We conclude that the high level of serum HMGB1, which preceded the increase in proinflammatory cytokines, is associated with postburn mortality.


Assuntos
Queimaduras/imunologia , Queimaduras/microbiologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Animais , Modelos Animais de Doenças , Feminino , Proteína HMGB1/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Camundongos , NF-kappa B/imunologia , Sepse/imunologia , Sepse/microbiologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/imunologia
7.
J Surg Res ; 263: 236-244, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33713955

RESUMO

BACKGROUND: Stromal interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) is now recognized as the main mechanism of the majority of nonexcitable cell calcium influx. Calcium overload is a primary mechanism of endothelial cell injury during systemic inflammatory response and sepsis. Whether STIM1-mediated SOCE plays a role in calcium overload in vascular endothelial cell injury remains unclear. MATERIALS AND METHODS: To explore the role of STIM1-gated SOCE in vascular endothelial cell calcium overload and inflammation, we established a human septic serum or lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) experimental system and derived ribonucleic acid interference (RNAi)-mediated STIM1, ORAI1 (orai gene [HGNC: 25896 Entrez Gene: 84876] coding protein, ORAI Calcium Release-Activated Calcium Modulator 1), and transient receptor potential channel 1 (TRPC1) (core components of store-operated Ca2+[SOC]) downregulated HUVECs, as well as STIM1 overinduced HUVECs. RESULTS: Our results show that sepsis serum or LPS stimulation increased STIM1 in HUVECs and increased all cytokines except for VEGF and the inflammatory mediators tumor necrosis factor, intercellular cell adhesion molecule-1, and endothelin-1 in a time-dependent manner. RNAi-mediated knockdown of STIM1 significantly inhibited serum or LPS-induced inflammatory cytokine expression, and STIM1 overexpression in HUVECs promoted LPS-mediated induction of these cytokines. Meanwhile, similar to the blocking effect of the specific SOC inhibitors Gd3+ and La3+ on LPS-induced calcium influx, RNAi-mediated depletion of STIM1 or the SOC proteins TRPC1 and ORAI1 could significantly inhibit serum or LPS-induced extracellular calcium influx, as well as the expression of the inflammatory cytokines tumor necrosis factor, intercellular cell adhesion molecule-1, and endothelin-1. Simultaneous downregulation of the SOCE core units TRPC1 and ORAI1 inhibited LPS-induced calcium influx and cytokine expression, which could not be restored by inducing STIM1. Forced expression of nuclear factor-κB (NF-κB) in HUVECs significantly induced STIM1 expression, whereas RNAi-mediated depletion of NF-κB significantly inhibited STIM1 mRNA levels and significantly reduced the thapsigargin-mediated SOCE calcium influx, which was similar to results with the NF-κB inhibitor wogonin. CONCLUSIONS: Septic serum stimulates the expression of STIM1, cytokines, and inflammatory mediators in HUVECs. STIM1-mediated SOCE is required for Ca2+ influx induced by LPS or septic serum and contributes cytokines and inflammatory mediators in septic serum-stimulated HUVECs. In addition, STIM1-mediated SOCE on Ca2+ influx by septic serum or LPS involves NF-κB signaling.


Assuntos
Queimaduras/sangue , Cálcio/metabolismo , Endotélio Vascular/patologia , Proteínas de Neoplasias/metabolismo , Sepse/imunologia , Molécula 1 de Interação Estromal/metabolismo , Adulto , Queimaduras/imunologia , Sinalização do Cálcio/imunologia , Endotélio Vascular/imunologia , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Sepse/sangue , Sepse/patologia , Soro/imunologia , Molécula 1 de Interação Estromal/genética
8.
Front Immunol ; 12: 586195, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33737924

RESUMO

Introduction: Burn injury is associated with a high risk of death. Whether a pattern of immune and inflammatory responses after burn is associated with outcome is unknown. The aim of this study was to explore the association between systemic immune and inflammatory responses and outcome in severely-ill burn patients. Materials and Methods: Innate immunity, adaptive immunity, activation and stress and inflammation biomarkers were collected at admission and days 2, 7, 14, and 28 in severely-ill adult burn patients. Primary endpoint was mortality at day 90, secondary endpoint was secondary infections. Healthy donors (HD) served as controls. Multiple Factorial Analysis (MFA) was used to identify patterns of immune response. Results: 50 patients were included. Age was 49.2 (44.2-54.2) years, total burn body surface area was 38.0% (32.7-43.3). Burn injury showed an upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. High interleukin-10 (IL-10) at admission was associated with risk of death. However, no cluster of immune/inflammatory biomarkers at early timepoints was associated with mortality. HLA-DR molecules on monocytes at admission were associated with bacterial infections and septic shock. Later altered immune/inflammatory responses in patients who died may had been driven by the development of septic shock. Conclusion: Burn injury induced an early and profound upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. Immune and inflammatory responses were associated with bacterial infection and septic shock. Absence of immune recovery patterns was associated with poor prognosis.


Assuntos
Infecções Bacterianas/etiologia , Queimaduras/complicações , Queimaduras/imunologia , Suscetibilidade a Doenças/imunologia , Choque Séptico/etiologia , Adulto , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/mortalidade , Infecções Bacterianas/terapia , Biomarcadores , Queimaduras/etiologia , Queimaduras/terapia , Comorbidade , Citocinas/metabolismo , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Mortalidade , Choque Séptico/diagnóstico , Choque Séptico/mortalidade , Choque Séptico/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Immunity ; 54(4): 648-659.e8, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33667383

RESUMO

Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury that is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by AIM2 inflammasome-dependent interleukin-1ß (IL-1ß) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury and challenges the current paradigms of post-injury lymphopenia.


Assuntos
Coinfecção/imunologia , Proteínas de Ligação a DNA/imunologia , Tolerância Imunológica/imunologia , Inflamassomos/imunologia , Transdução de Sinais/imunologia , Animais , Apoptose/imunologia , Infecções Bacterianas/imunologia , Queimaduras/imunologia , Queimaduras/microbiologia , Coinfecção/microbiologia , Humanos , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/microbiologia , Linfócitos T/imunologia
10.
NPJ Biofilms Microbiomes ; 7(1): 8, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495449

RESUMO

Bacterial biofilms cause 65% of all human infections and are highly resistant to antibiotic therapy but lack specific treatments. To provide a human organoid model for studying host-microbe interplay and enabling screening for novel antibiofilm agents, a human epidermis organoid model with robust methicillin-resistant Staphylococcus aureus (MRSA) USA300 and Pseudomonas aeruginosa PAO1 biofilm was developed. Treatment of 1-day and 3-day MRSA and PAO1 biofilms with antibiofilm peptide DJK-5 significantly and substantially reduced the bacterial burden. This model enabled the screening of synthetic host defense peptides, revealing their superior antibiofilm activity against MRSA compared to the antibiotic mupirocin. The model was extended to evaluate thermally wounded skin infected with MRSA biofilms resulting in increased bacterial load, cytotoxicity, and pro-inflammatory cytokine levels that were all reduced upon treatment with DJK-5. Combination treatment of DJK-5 with an anti-inflammatory peptide, 1002, further reduced cytotoxicity and skin inflammation.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Modelos Biológicos , Organoides/microbiologia , Antibacterianos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carga Bacteriana/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Queimaduras/tratamento farmacológico , Queimaduras/imunologia , Queimaduras/microbiologia , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Organoides/efeitos dos fármacos , Organoides/imunologia , Organoides/lesões , Pseudomonas aeruginosa/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/lesões , Pele/microbiologia
11.
Surg Infect (Larchmt) ; 22(1): 88-94, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32460632

RESUMO

Background: Viral infections after burns are less common than bacterial infections but usually occur in the more severely burned patients and have been associated with poor outcomes. Methods: Retrospective reviews and case series were examined to provide an overview of the management of viral infections in the burn patient. Results: The most common viral pathogens in these patients are the herpesviruses, which include herpes simplex, varicella zoster, cytomegalovirus, and human herpesvirus 6. Established viral infections that may complicate patient management include human immunodeficiency virus, hepatitis B and C, and, more recently, the novel coronavirus SARS-CoV-2. Herpesvirus infections can occur as primary or nosocomial pathogens but clinical manifestations most commonly are re-activation of latent viral infection. Because of the paucity of data in the burn population, much of the evidence for specific treatments is extrapolated from patients with severe immunosuppression or critical illness. Antiviral therapy is employed for the burn patient with herpesvirus infections. This is an area of active study, and further research is needed to better understand the risks, clinical manifestations, and attributable morbidity and mortality of viral infections. Conclusions: Major burn injury results in immunosuppression and viral infection in a small number of patients. Recognition and antiviral therapy are employed, but additional studies are necessary to improve outcomes in these patients.


Assuntos
Queimaduras/epidemiologia , Queimaduras/imunologia , Viroses/epidemiologia , Antivirais/uso terapêutico , Queimaduras/tratamento farmacológico , Queimaduras/virologia , COVID-19/epidemiologia , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Infecções por Herpesviridae/diagnóstico por imagem , Infecções por Herpesviridae/epidemiologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Mediadores da Inflamação/metabolismo , Estudos Retrospectivos , Infecções por Roseolovirus/tratamento farmacológico , Infecções por Roseolovirus/epidemiologia , SARS-CoV-2 , Viroses/tratamento farmacológico , Viroses/mortalidade
12.
J Leukoc Biol ; 109(3): 645-656, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32531832

RESUMO

CD4+ regulatory T cells (Tregs) are acutely activated by traumatic injury, which suggests that they may react to injury with similar kinetics as memory T cells. Here, we used a mouse burn trauma model to screen for memory-like T cell responses to injury by transferring T cells from sham or burn CD45.1 mice into CD45.2 mice and performing secondary injuries in recipient mice. Among all T cell subsets that were measured, only Tregs expanded in response to secondary injury. The expanded Tregs were a CD44high /CD62Llow subpopulation, markers indicative of memory T cells. CyTOF (cytometry by time-of-flight) mass cytometry was used to demonstrate that injury-expanded Tregs expressed higher levels of CD44, CTLA-4, ICOS, GITR, and Helios than Tregs from noninjured mice. Next, we tested whether a similar population of Tregs might react acutely to burn trauma. We observed that Tregs with a phenotype that matched the injury-expanded Tregs were activated by 6 h after injury. To test if Treg activation by trauma requires functional MHC class II, we measured trauma-induced Treg activation in MHC class II gene deficient (MHCII-/- ) mice or in mice that were given Fab fragment of anti-MHC class II antibody to block TCR activation. Injury-induced Treg activation occurred in normal mice but only partial activation was detected in MHCII-/- mice or in mice that were given Fab anti-MHCII antibody. These findings demonstrate that trauma activates a memory-like Treg subpopulation and that Treg activation by injury is partially dependent on TCR signaling by an MHC class II dependent mechanism.


Assuntos
Memória Imunológica , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Ferimentos e Lesões/imunologia , Animais , Biomarcadores/metabolismo , Queimaduras/imunologia , Queimaduras/patologia , Proliferação de Células , Antígenos de Histocompatibilidade Classe II/metabolismo , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Baço/patologia , Ferimentos e Lesões/patologia
13.
Inflamm Res ; 70(1): 51-65, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33245371

RESUMO

A burn insult generally sustains a hypovolemic shock due to a significant loss of plasma from the vessels. The burn injury triggers the release of various mediators, such as reactive oxygen species (ROS), cytokines, and inflammatory mediators. Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), stemming from foreign microbial discharge and damaged tissue or necrotic cells from the burn-injured site, enter the systemic circulation, activate toll-like receptors (TLRs), and trigger the excessive secretion of cytokines and inflammatory mediators. Inflammation plays a vital role in remodeling an injured tissue, detoxifying toxins, and helps in the healing process. A transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), contributes to a variety of physiological and pathological conditions, including immune response, cell death, cell survival, and inflammatory processes. During the pathogenesis of a burn wound, upregulation of various cytokines and growth factors lead to undesirable tissue inflammation. Thus, NF-κB, a dominant moderator of inflammation, needs to be altered to prove beneficial to the treatment of burns or other inflammation-associated diseases. This review addresses the relationship between NF-κB and elevated inflammation in a burn condition that could potentially be altered to induce an early wound-healing mechanism of burn wounds.


Assuntos
Queimaduras/imunologia , NF-kappa B/imunologia , Animais , Queimaduras/complicações , Humanos , Inflamação/etiologia , Inflamação/imunologia , Espécies Reativas de Oxigênio/imunologia
14.
JCI Insight ; 6(2)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33320841

RESUMO

Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at the cellular level. To deconvolute the trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors, which can be traced back to myeloid progenitors. These changes were largely recapitulated in the human single-cell analysis. We generalized the major changes in human CD14+ monocytes into 6 signatures, which further defined 2 trauma patient subtypes (SG1 vs. SG2) identified in the whole-blood leukocyte transcriptome in the initial 12 hours after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction, and a higher incidence of infection and noninfectious complications. The 2 patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.


Assuntos
Ferimentos e Lesões/genética , Ferimentos e Lesões/imunologia , Adulto , Animais , Células da Medula Óssea/imunologia , Queimaduras/sangue , Queimaduras/genética , Queimaduras/imunologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RNA-Seq , Sepse/sangue , Sepse/genética , Sepse/imunologia , Choque Hemorrágico/sangue , Choque Hemorrágico/genética , Choque Hemorrágico/imunologia , Análise de Célula Única , Fatores de Tempo , Transcriptoma , Ferimentos e Lesões/classificação , Adulto Jovem
15.
Sci Rep ; 10(1): 21818, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311597

RESUMO

Burn wounds are highly susceptible sites for colonization and infection by bacteria and fungi. Large wound surface, impaired local immunity, and broad-spectrum antibiotic therapy support growth of opportunistic fungi such as Candida albicans, which may lead to invasive candidiasis. Currently, it remains unknown whether depressed host defenses or fungal virulence drive the progression of burn wound candidiasis. Here we established an ex vivo burn wound model, where wounds were inflicted by applying preheated soldering iron to human skin explants, resulting in highly reproducible deep second-degree burn wounds. Eschar removal by debridement allowed for deeper C. albicans penetration into the burned tissue associated with prominent filamentation. Active migration of resident tissue neutrophils towards the damaged tissue and release of pro-inflammatory cytokine IL-1ß accompanied the burn. The neutrophil recruitment was further increased upon supplementation of the model with fresh immune cells. Wound area and depth decreased over time, indicating healing of the damaged tissue. Importantly, prominent neutrophil presence at the infected site correlated to the limited penetration of C. albicans into the burned tissue. Altogether, we established a reproducible burn wound model of candidiasis using ex vivo human skin explants, where immune responses actively control the progression of infection and promote tissue healing.


Assuntos
Queimaduras/imunologia , Candida albicans/imunologia , Candidíase/imunologia , Neutrófilos/imunologia , Pele/imunologia , Infecção dos Ferimentos/imunologia , Adulto , Queimaduras/microbiologia , Queimaduras/patologia , Candidíase/patologia , Feminino , Humanos , Interleucina-1beta/imunologia , Pessoa de Meia-Idade , Neutrófilos/patologia , Pele/microbiologia , Pele/patologia , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/patologia
16.
Int J Mol Sci ; 21(17)2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32872240

RESUMO

Androgens have been known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. The aim of this study is to investigate the role of dihydrotestosterone (DHT) as a new therapeutic approach in treating major burn injury. In the present study, mice received systemic androgen treatment post major burn injury. Wound healing rate and body weight were monitored over 21 days. The serum level of inflammatory cytokines/chemokines were measured using multiplex immunoassays. In addition, splenocyte enumeration was performed by flow cytometry. Healing phases of inflammation, re-epithelialization, cell proliferation and collagen deposition were also examined. In results, DHT treated mice lost less weight and displayed accelerated wound healing but has no impact on hypermetabolism. Mice, after burn injury, displayed acute systemic inflammatory responses over 21 days. DHT treatment shortened the systemic inflammatory response with reduced splenic weight and monocyte numbers on day 14 and 21. DHT treatment also reduced wound infiltrating macrophage numbers. In conclusion, DHT treatment facilitates local wound healing by accelerating the resolution of inflammation, but not through alterations of post-burn hypermetabolic response.


Assuntos
Androgênios/administração & dosagem , Queimaduras/tratamento farmacológico , Di-Hidrotestosterona/administração & dosagem , Cicatrização/efeitos dos fármacos , Androgênios/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Queimaduras/sangue , Queimaduras/imunologia , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/sangue , Di-Hidrotestosterona/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Baço/efeitos dos fármacos , Baço/imunologia
17.
Front Immunol ; 11: 1481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793203

RESUMO

Epidemiological studies have demonstrated that survivors of acute burn trauma are at long-term increased risk of developing a range of morbidities. The mechanisms underlying this increased risk remain unknown. This study aimed to determine whether burn injury leads to sustained immune dysfunction that may underpin long-term morbidity. Plasma and peripheral blood mononuclear cells were collected from 36 pediatric burn survivors >3 years after a non-severe burn injury (<10% total body surface area) and from age/sex-matched non-injured controls. Circulating cytokine and vaccine antibody levels were assessed using multiplex immunoassays and cell profiles compared using a panel of 40 metal-conjugated antibodies and mass cytometry. TNF-α (1.31-fold change from controls), IL-2 (1.18-fold), IL-7 (1.63-fold), and IFN-γ (1.18-fold) were all significantly elevated in the burn cohort. Additionally, burn survivors demonstrated diminished antibody responses to the diphtheria, tetanus, and pertussis vaccine antigens. Comparisons between groups using unsupervised clustering identified differences in proportions of clusters within T-cells, B-cells and myeloid cells. Manual gating confirmed increased memory T-regulatory and central memory CD4+ T-cells, with altered expression of T-cell, B-cell, and dendritic cell markers. Conclusions: This study demonstrates a lasting change to the immune profile of pediatric burn survivors, and highlights the need for further research into post-burn immune suppression and regulation.


Assuntos
Queimaduras/imunologia , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Leucócitos Mononucleares/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Anticorpos Antibacterianos/sangue , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Imunomodulação , Imunofenotipagem , Lactente , Masculino
18.
J Immunol ; 205(5): 1189-1197, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32839211

RESUMO

Thermal injury is often associated with a proinflammatory state resulting in serious complications. After a burn, the innate immune system is activated with subsequent immune cell infiltration and cytokine production. Although the innate immune response is typically beneficial, an excessive activation leads to cytokine storms, multiple organ failure, and even death. This overwhelming immune response is regulated by damage-associated molecular patterns (DAMPs). DAMPs are endogenous molecules that are actively secreted by immune cells or passively released by dead or dying cells that can bind to pathogen recognition receptors in immune and nonimmune cells. Recent studies involving animal models along with human studies have drawn great attention to the possible pathological role of DAMPs as an immune consequence of thermal injury. In this review, we outline DAMPs and their function in thermal injury, shedding light on the mechanism of sterile inflammation during tissue injury and identifying new immune targets for treating thermal injury.


Assuntos
Queimaduras/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Animais , Síndrome da Liberação de Citocina/imunologia , Humanos
19.
Front Immunol ; 11: 876, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32477354

RESUMO

Infection is a common and severe complication of burn injury: Sepsis accounts for 47% of postburn mortality. Burn-induced T cell suppression likely contributes to the increased infection susceptibility in burn patients. However, little is known about the kinetics of T cell dysfunction after burn and its underlying mechanisms. In this study, we show in a murine scald injury model that T cell activation of both CD4+ and CD8+ T cells as well as T cell cytokine production is suppressed acutely and persistently for at least 11 days after burn injury. Purified T cells from scald-injured mice exhibit normal T cell functions, indicating an extrinsically mediated defect. We further show that T cell dysfunction after burn appears to be cell-to-cell contact dependent and can be ameliorated by depletion of myeloid-derived suppressor cells. These cells expand after burn injury, particularly a subset expressing the checkpoint inhibitor CD172a, and infiltrate germinal centers. Expression of CD172a appears to be driven by ingestion of immature reticulocytes. Immature reticulocytes are drastically increased in the spleen of scald mice and may contribute to immunosuppression through more direct mechanisms as well. Overall, our study newly identifies two cell populations, myeloid-derived suppressor cells and immature reticulocytes, as well as the CD47/CD172a-signaling pathways as mediators of T cell suppressors after burn and thus opens up new research opportunities in the search for new therapies to combat increased infection susceptibility and the associated morbidity and mortality in burn victims.


Assuntos
Antígenos de Diferenciação/metabolismo , Queimaduras/metabolismo , Antígeno CD47/metabolismo , Células Supressoras Mieloides/imunologia , Receptores Imunológicos/metabolismo , Reticulócitos/imunologia , Linfócitos T/imunologia , Animais , Antígenos Ly/metabolismo , Queimaduras/imunologia , Células Cultivadas , Tolerância Imunológica , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos , Transdução de Sinais
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