RESUMEN
BACKGROUND: Soluble suppression of tumorigenicity 2 (sST2), a decoy receptor for interleukin (IL)-33, has emerged as a novel biomarker in various disease processes. Recent studies have elucidated the role of the sST2/IL-33 complex in modulating the balance of Th1/Th2 immune responses after tissue stress. However, the role of sST2 as a biomarker after traumatic injury remains unclear. To address this, we evaluated serum sST2 correlations with mortality and in-hospital adverse outcomes as endpoints in blunt trauma patients. METHODS: We retrospectively analyzed clinical and biobank data of 493 blunt trauma victims 472 survivors (mean age: 48.4 ± 0.87; injury severity score [ISS]: 19.6 ± 0.48) and 19 nonsurvivors (mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) admitted to the intensive care unit. Given the confounding impact of age on the inflammatory response, we derived a propensity-matched survivor subgroup (n = 19; mean age: 59 ± 3; ISS: 23.4 ± 2) using an IBM SPSS case-control matching algorithm. Serial blood samples were obtained from all patients (3 samples within the first 24 h and then once daily from day [D] 1 to D5 after injury). sST2 and twenty-nine inflammatory biomarkers were assayed using enzyme-linked immunosorbent assay and Luminex, respectively. Two-way analysis of variance on ranks was used to compare groups (P < 0.05). Spearman rank correlation was performed to determine the association of circulating sST2 levels with biomarker levels and in-hospital clinical outcomes. RESULTS: Circulating sST2 levels of the nonsurvivor cohort were statistically significantly elevated at 12 h after injury and remained elevated up to D5 when compared either to the overall 472 survivor cohort or a matched 19 survivor subcohort. Admission sST2 levels obtained from the first blood draw after injury in the survivor cohort correlated positively with admission base deficit (correlation coefficient [CC] = 0.1; P = 0.02), international normalized ratio (CC = 0.1, P = 0.03), ISS (CC = 0.1, P = 0.008), and the average Marshall multiple organ dysfunction score between D2 and D5 (CC = 0.1, P = 0.04). Correlations with ISS revealed a positive correlation of ISS with plasma sST2 levels across the mild ISS (CC = 0.47, P < 0.001), moderate ISS (CC = 0.58, P < 0.001), and severe ISS groups (CC = 0.63, P < 0.001). Analysis of biomarker correlations in the matched survivor group over the initial 24 h after injury showed that sST2 correlates strongly and positively with IL-4 (CC = 0.65, P = 0.002), IL-5 (CC = 0.57, P = 0.01), IL-21 (CC = 0.52, P = 0.02), IL-2 (CC = 0.51, P = 0.02), soluble IL-2 receptor-α (CC = 0.5, P = 0.02), IL-13 (CC = 0.49, P = 0.02), and IL-17A (CC = 0.48, P = 0.03). This was not seen in the matched nonsurvivor group. sST2/IL-33 ratios were significantly elevated in nonsurvivors and patients with severe injury based on ISS ≥ 25. CONCLUSIONS: Elevations in serum sST2 levels are associated with poor clinical trajectories and mortality after blunt trauma. High sST2 coupled with low IL-33 associates with severe injury, mortality, and worse clinical outcomes. These findings suggest that sST2 could serve as an early prognostic biomarker in trauma patients and that sustained elevations of sST2 could contribute to a detrimental suppression of IL-33 bioavailability in patients with high injury severity.
Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1/sangre , Heridas no Penetrantes/mortalidad , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Mortalidad Hospitalaria , Humanos , Puntaje de Gravedad del Traumatismo , Unidades de Cuidados Intensivos/estadística & datos numéricos , Interleucina-33/sangre , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Pronóstico , Estudios Retrospectivos , Heridas no Penetrantes/sangre , Heridas no Penetrantes/diagnósticoRESUMEN
BACKGROUND: The immunosuppression and immune dysregulation that follows severe injury includes type 2 immune responses manifested by elevations in interleukin (IL) 4, IL5, and IL13 early after injury. We hypothesized that IL33, an alarmin released early after tissue injury and a known regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury. METHODS AND FINDINGS: Blunt trauma patients admitted to the trauma intensive care unit of a level I trauma center were enrolled in an observational study that included frequent blood sampling. Dynamic changes in IL33 and soluble suppression of tumorigenicity 2 (sST2) levels were measured in the plasma and correlated with levels of the type 2 cytokines and nosocomial infection. Based on the observations in humans, mechanistic experiments were designed in a mouse model of resuscitated hemorrhagic shock and tissue trauma (HS/T). These experiments utilized wild-type C57BL/6 mice, IL33-/- mice, B6.C3(Cg)-Rorasg/sg mice deficient in group 2 innate lymphoid cells (ILC2), and C57BL/6 wild-type mice treated with anti-IL5 antibody. Severely injured human blunt trauma patients (n = 472, average injury severity score [ISS] = 20.2) exhibited elevations in plasma IL33 levels upon admission and over time that correlated positively with increases in IL4, IL5, and IL13 (P < 0.0001). sST2 levels also increased after injury but in a delayed manner compared with IL33. The increases in IL33 and sST2 were significantly greater in patients that developed nosocomial infection and organ dysfunction than similarly injured patients that did not (P < 0.05). Mechanistic studies were carried out in a mouse model of HS/T that recapitulated the early increase in IL33 and delayed increase in sST2 in the plasma (P < 0.005). These studies identified a pathway where IL33 induces ILC2 activation in the lung within hours of HS/T. ILC2 IL5 up-regulation induces further IL5 expression by CXCR2+ lung neutrophils, culminating in early lung injury. The major limitations of this study are the descriptive nature of the human study component and the impact of the potential differences between human and mouse immune responses to polytrauma. Also, the studies performed did not permit us to make conclusions about the impact of IL33 on pulmonary function. CONCLUSIONS: These results suggest that IL33 may initiate early detrimental type 2 immune responses after trauma through ILC2 regulation of neutrophil IL5 production. This IL33-ILC2-IL5-neutrophil axis defines a novel regulatory role for ILC2 in acute lung injury that could be targeted in trauma patients prone to early lung dysfunction.
Asunto(s)
Regulación de la Expresión Génica , Inmunidad Humoral , Interleucina-33/metabolismo , Interleucina-5/genética , Linfocitos/inmunología , Heridas y Lesiones/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-33/sangre , Interleucina-5/inmunología , Pulmón/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Estudios Retrospectivos , Choque Hemorrágico/complicaciones , Choque Hemorrágico/inmunología , Heridas y Lesiones/etiología , Heridas y Lesiones/genética , Adulto JovenRESUMEN
We hypothesized that elevated base deficit (BD) ≥ 4 mEq/L upon admission could be associated with an altered inflammatory response, which in turn may impact differential clinical trajectories. Using clinical and biobank data from 472 blunt trauma survivors, 154 patients were identified after excluding patients who received prehospital IV fluids or had alcohol intoxication. From this subcohort, 84 patients had a BD ≥ 4 mEq/L and 70 patients with BD < 4 mEq/L. Three samples within the first 24 h were obtained from all patients and then daily up to day 7 after injury. Twenty-two cytokines and chemokines were assayed using Luminex™ and were analyzed using two-way ANOVA and dynamic network analysis (DyNA). Multiple mediators of the innate and lymphoid immune responses in the BD ≥ 4 group were elevated differentially upon admission and up to 16 h after injury. DyNA revealed a higher, sustained degree of interconnectivity of the inflammatory response in the BD ≥ 4 patients during the initial 16 h after injury. These results suggest that elevated admission BD is associated with differential immune/inflammatory pathways, which subsequently could predispose patients to follow a complicated clinical course.
Asunto(s)
Desequilibrio Ácido-Base/sangre , Desequilibrio Ácido-Base/inmunología , Inflamación/sangre , Inflamación/inmunología , Heridas y Lesiones/sangre , Heridas y Lesiones/inmunología , Análisis de Varianza , Quimiocinas/sangre , Quimiocinas/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Heridas no Penetrantes/sangre , Heridas no Penetrantes/inmunologíaRESUMEN
BACKGROUND: Although the role of TLR4 in driving inflammation and organ injury after hemorrhagic shock and resuscitation (H/R) is well established, the role of TLR2-another receptor for damage-associated molecular pattern (DAMP) molecules-is not. In this study, we used a combination of TLR2 and wild type (WT) mice treated with anti-TLR2 and anti-TLR4 neutralizing monoclonal antibodies (mAb) to discern the contribution of TLR2 relative to TLR4 to the systemic inflammatory response in murine H/R. MATERIAL AND METHODS: WT mice, TLR2, and WT mice receiving an anti-TLR2 or an anti-TLR4 mAB (given as a pretreatment) were sacrificed at 6 or 20 h post-H/R. Bone marrow TLR2/WT chimeric mice were created to assess the importance of immune and nonimmune cell-associated TLR2. RESULTS: TLR2 mice subjected to H/R exhibited significantly less liver damage and lower markers of systemic inflammation only at 20 h. Bone marrow chimeric mice using combinations of TLR2 mice and WT mice demonstrated that TLR2 on non-bone marrow derived cells played a dominant role in the differences at 20 h. Interestingly, WT mice treated with anti-TLR2 mAB demonstrated a reduction in organ damage and systemic inflammation at both 6 and 20 h following H/R. A combination of anti-TLR2 mAB and anti-TLR4 mAB showed that both receptors drive IP-10 and KC levels and that there is cooperation for increases in IL-6, MIG, and MCP-1 levels between TLR2 and TLR4. CONCLUSION: These data also support the conclusion that TLR2 and TLR4 act in concert as important receptors in the host immune response to H/R.
Asunto(s)
Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Choque Hemorrágico/tratamiento farmacológico , Choque Hemorrágico/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Médula Ósea , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Resucitación , Choque Hemorrágico/inmunología , Choque Hemorrágico/terapia , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 4/antagonistas & inhibidoresRESUMEN
BACKGROUND: While the prevalence of obesity in IBD patients is rapidly increasing, it is unclear if obesity impacts surgical outcomes in this population. We aim to investigate the effects of BMI on perioperative and postoperative outcomes in IBD patients by stratifying patients into BMI groups and comparing outcomes between these groups. METHODS: This is a retrospective cohort study where IBD patients who underwent intestinal surgeries between the years of 2000 to 2014 were identified. The patients were divided into groups based on BMI: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), and obese (BMI ≥30). Preoperative patient demographics, operative variables, and postoperative complications were collected and compared between BMI groups. RESULTS: A total of 391 surgeries were reviewed (34 underweight, 187 normal weight, 105 overweight, and 65 obese) from 325 patients. No differences were observed in preoperative patient demographics, type of IBD, preoperative steroid or biologic mediator use, or mean laboratory values. No differences were observed in percent operative procedures with anastomosis, surgeries converted to open, estimated blood loss, intraoperative complications, and median operative time. Thirty-day postoperative complication rates including total complications, wound infection, or anastomotic leak were similar between groups. There was a statistically significant increased postoperative bleeding risk (p = 0.029) in underweight patients. The relative percent for increased postoperative bleeding risk between BMI groups was as follows: 2.9% in underweight, zero in normal weight, 2.9% in overweight, and zero in obese. CONCLUSION: Obesity does not appear to impact intraoperative variables nor does obesity appear to worsen postoperative complication rates in IBD patients.
Asunto(s)
Enfermedades Inflamatorias del Intestino/cirugía , Complicaciones Intraoperatorias , Obesidad/complicaciones , Complicaciones Posoperatorias , Delgadez/complicaciones , Adulto , Índice de Masa Corporal , Femenino , Humanos , Peso Corporal Ideal , Masculino , Persona de Mediana Edad , Tempo Operativo , Sobrepeso/complicaciones , Periodo Posoperatorio , Estudios RetrospectivosRESUMEN
Despite the widespread role of transforming growth factor-beta3 (TGFbeta3) in wound healing and tissue regeneration, its long-term controlled release has not been demonstrated. Here, we report microencapsulation of TGFbeta3 in poly-d-l-lactic-co-glycolic acid (PLGA) microspheres and determine its bioactivity. The release profiles of PLGA-encapsulated TGFbeta3 with 50:50 and 75:25 PLA:PGA ratios differed throughout the experimental period. To compare sterilization modalities of microspheres, bFGF was encapsulated in 50:50 PLGA microspheres and subjected to ethylene oxide (EO) gas, radio-frequency glow discharge (RFGD), or ultraviolet (UV) light. The release of bFGF was significantly attenuated by UV light, but not significantly altered by either EO or RFGD. To verify its bioactivity, TGFbeta3 (1.35 ng/mL) was control-released to the culture of human mesenchymal stem cells (hMSC) under induced osteogenic differentiation. Alkaline phosphatase staining intensity was markedly reduced 1 week after exposing hMSC-derived osteogenic cells to TGFbeta3. This was confirmed by lower alkaline phosphatase activity (2.25 +/- 0.57 mU/mL/ng DNA) than controls (TGFbeta3- free) at 5.8 +/- 0.9 mU/mL/ng DNA (p < 0.05). Control-released TGFbeta3 bioactivity was further confirmed by lack of significant differences in alkaline phosphatase upon direct addition of 1.35 ng/mL TGFbeta3 to cell culture (p > 0.05). These findings provide baseline data for potential uses of microencapsulated TGFbeta3 in wound healing and tissue-engineering applications.