Post-traumatic Multiple Organ Dysfunction Syndrome Research Articles

Inhibition of the JAK/STAT Pathway With Baricitinib Reduces the Multiple Organ Dysfunction Caused by Hemorrhagic Shock in Rats.

The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB, and NLRP3 caused by HS. Posttraumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown. An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB, and NLRP3 pathways were analyzed by western blotting in the kidney and liver. We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB, and NLRP3 pathways caused by HS in the rat. Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.

Selective Inhibition of IL-6 Trans-Signaling Has No Beneficial Effect on the Posttraumatic Cytokine Release after Multiple Trauma in Mice.

While improvements in pre-hospital and in-hospital care allow more multiple trauma patients to advance to intensive care, the incidence of posttraumatic multiple organ dysfunction syndrome (MODS) is on the rise. Herein, the influence of a selective IL-6 trans-signaling inhibition on posttraumatic cytokine levels was investigated as an approach to prevent MODS caused by a dysbalanced posttraumatic immune reaction. Therefore, the artificial IL-6 trans-signaling inhibitor sgp130Fc was deployed in a murine multiple trauma model (femoral fracture plus bilateral chest trauma). The traumatized mice were treated with sgp130Fc (FP) and compared to untreated mice (WT) and IL-6 receptor knockout mice (RKO), which received the same traumas. The overall trauma mortality was 4.4%. Microscopic pulmonary changes were apparent after multiple trauma and after isolated bilateral chest trauma. Elevated IL-6, MCP-3 and RANTES plasma levels were measured after trauma, indicating a successful induction of a systemic inflammatory reaction. Significantly reduced IL-6 and RANTES plasma levels were visible in RKO compared to WT. Only a little effect was visible in FP compared to WT. Comparable cytokine levels in WT and FP indicate neither a protective nor an adverse effect of sgp130Fc on the cytokine release after femoral fracture and bilateral chest trauma.

Neutrophil-derived long noncoding RNA IL-7R predicts development of multiple organ dysfunction syndrome in patients with trauma.

Overactive neutrophils are thought to be key drivers in the development of post-traumatic multiple organ dysfunction syndrome (MODS). Little is known about the role of inflammation-related lnc-IL7R in trauma. Thus, we aimed to explore the association between neutrophil-derived lnc-IL7R and post-traumatic MODS. Total RNA was extracted from the isolated circulating neutrophils in 60 patients with trauma and 33 healthy volunteers for lnc-IL7R expression determination by real-time PCR. The correlation of lnc-IL7R expression with disease severity and the development of post-traumatic MODS was analyzed. The lnc-IL7R levels were significantly lower in trauma patients, especially in those with severe trauma [Injury Severity Score (ISS) ≥ 16], and correlated negatively with the ISS, Acute Physiology and Chronic Health Evaluation II score, and length of ICU stay. The lnc-IL7R levels were also significantly decreased in patients who developed MODS than in those who did not. Lnc-IL7R was an independent predictor of MODS [odds ratio (OR) 0.654, (0.435-0.982), p = 0.041]. The area under the curve for predicting post-traumatic MODS was 0.799 (sensitivity 76.9%, specificity 71.4%), with a cutoff value of 0.024. Neutrophil-derived lnc-IL7R is an independent predictor of post-traumatic MODS; therefore, it could be a useful predictive marker for MODS.

Predictive Value of Osteoprotegerin and Neutrophil Gelatinase-associated Lipocalin on Multiple Organ Failure in Multiple Trauma.

Multiple organ dysfunction syndrome (MODS) is the leading cause of late posttraumatic mortality. This study analyzed the prognostic values of osteoprotegerin (OPG) and neutrophil gelatinase-associated lipocalin (NGAL/lipocalin 2) compared to interleukin-6 (IL-6) in multiply injured patients. A retrospective observational cohort study on multiply injured patients with an injury severity score (ISS) of ≥16 was performed. OPG, NGAL and IL-6 blood concentrations were measured. Statistical analysis comprised receiver-operating-characteristic (ROC) analysis with the corresponding area under the curve (AUC). Thirty-nine patients with a mean ISS of 34±11 were included. Fourteen patients (36%) developed MODS and 8 patients (21%) died. Plasma levels of NGAL, OPG, and IL-6 were significantly elevated in the MODS+ group. Each biomarker positively correlated with MODS score and diagnosis of MODS. NGAL and OPG might be indicative of MODS and could have the potential to be biomarkers in the early detection of patients at risk of posttraumatic MODS.

A phosphoproteomic study reveals shp-1 cleavage reprograms LPS signaling via a PI-3K/NF-κB and mTORC1 related mechanism

The reprogrammed lipopolysaccharide (LPS) pathway has been reported to render patients more susceptible to the development of post-traumatic multiple organ dysfunction syndrome (MODS). To facilitate thorough understanding of this mechanism, a phosphoproteomic study was utilized to screen the potential signaling molecules. Interestingly, a truncated form of Src homology 2-domain-containing tyrosine phosphatase 1 (shp-1) emerged in human THP-1 macrophages sequentially treated with H2O2 and LPS and not with either of the treatments alone. Subsequent immunoblot analysis confirmed the cleavage of shp-1 and reduction of shp-1 activity in rat alveolar macrophages, mast cells, and neutrophils. Mechanistically, calpain is essential but not sufficient for shp-1 cleavage. In addition, shp-1 cleavage renders the activation of phosphatidylinositol 3-kinase (PI-3K)/nuclear factor-κB (NF-κB) and mechanistic target of rapamycin complex 1 (mTORC1) in macrophages, resulting in enhanced cytokine induced neutrophil chemoattractant (CINC) secretion, which is critical for neutrophil recruitment in MODS. On the other hand, shp-1 cleavage results in the activation of PI-3K/Akt, enhancing the survival of neutrophils. Collectively, these results highlight the cleavage of shp-1 as a critical event in reprogramming LPS pathway to promote both neutrophil recruitment and survival and provide a novel mechanistic framework for the investigation of the post-traumatic MODS.

Relationgship between value of nitric oxide synthase in peripheral blood monocyte and post-traumatic multiple organ dysfunction syndrome in severely traumatic patients

目的 探讨巨噬细胞一氧化氮合酶(NOS)表达在创伤后多器官功能障碍综合征(MODS)发生发展中的可能作用与机制.方法 采用分光光度测定法动态检测83例严重创伤患者外周血单核细胞NOS活性,比较分析MODS与非MODS组间、MODS患者存活与死亡组间外周血单核细胞NOS水平的差异.结果 (1)与健康对照组相比,非MODS组与MODS组外周血单核细胞NOS活性峰值(u/L)均明显升高(P＜0.01),MODS组与非MODS组间也有明显差异(P＜0.01),MODS患者死亡组较存活组更高(P＜0.01).(2)动态观察显示,严重创伤患者无论是否并发MODS,其外周血单核细胞NOS活性于伤后第1天即见升高,但非MODS组升高幅度小且于3～5 d即恢复,而MODS组升高幅度较大且持续时间较长.峰值出现于MODS发生后第1天并持续到病情得以控制时才见下降,死亡组升高幅度更大并一直保持在峰值水平.结论 创伤患者巨噬细胞NOS异常表达参与了创伤后MODS的发生、发展过程。

L-Selectin shows time and gender dependency in association with MODS

Background: Recent investigations have demonstrated gender related immunologic alterations after trauma. These complications arise due to polymorphonuclear granulocytes (PMN) interacting with endothelium via l-selectin. Therefore, the purpose of this study was to investigate gender related differences in the expression of l-selectin in relation to posttraumatic multiple organ dysfunction syndrome (MODS). Methods: Multiply injured patients were prospectively entered in the study. MODS was determined using the Denver score. The concentration of l-selectin on the surface of PMN was determined using flow cytometry during a 14 days’ period. Results: 48 patients were included in the study. The kinetics of l-selectin were different comparing male and female patients. Male patients with MODS initially showed a rapid decrease of surface l-selectin from 80 to 20 ng/ml. A return to admission levels was related to MODS. Male patients without MODS displayed elevated l-selectin levels up to 140 ng/ml. Female patients, however, all showed an initial rapid decrease of l-selectin to 20 ng/ml. Women who developed posttraumatic MODS had significantly increased levels up to 110 ng/ml before development of MODS developed. Conclusions: We feel that a gender related dimorphism in the initial l-selectin expression following trauma exists and is associated with MODS. These findings indicate new therapeutic means for the treatment of MODS. Therapies should be timely and gender dependently coordinated.

Effects of continuous veno-venous hemofiltration on the serum levels of NO and TNF-α and short-term prognosis in patients with post-traumatic multiple organ dysfunction syndrome

目的 探讨连续性静-静脉血液滤过(CVVH)对创伤后多器官功能障碍综合征(MODS)病人血清一氧化氮(NO)与α-肿瘤坏死因子(TNF-α)浓度及近期预后的影响.方法 17例创伤后MODS病人一经确诊即行床边CVVH.CVVH之前和之后6 h取血和超滤液检测NO与TNF-α浓度.结果 CVVH干预后6 h血清NO浓度峰值与TNF-α浓度峰值与CVVH干预之前比较均有显著性统计学意义,CVVH干预组住院病死率明显低于对照组,滤过液中也能检测到较高浓度的NO和TNF-α.结论 CVVH能够有效清除创伤后MODS病人血中过高的NO和TNF-α并明显改善近期预后。

Early detection of increased tumour necrosis factor alpha (TNFalpha) and soluble TNF receptor protein plasma levels after trauma reveals associations with the clinical course.

The inflammatory response after trauma includes tumour necrosis factor alpha (TNFalpha) as pro-inflammatory cytokine. Furthermore, both soluble TNF receptor proteins (sTNF-R1 and sTNF-R2) were described to influence the post-traumatic inflammatory response and organ dysfunction. From 47 trauma patients, blood samples were obtained at the scene of accident, at hospital admission, after 4 h, 12 h, and 24 h, and daily until day 6. Plasma levels of TNFalpha, sTNFR1 and sTNF-R2 were measured by enzyme immunoassay (EIA) and analysed comparing clinical parameters such as injury scores (ISS, AIS), development of multiple organ dysfunction syndrome (MODS) and/or systemic inflammatory response syndrome (SIRS), and outcome. Significant changes were observed in a time-dependent manner: TNFalpha and soluble TNF receptor levels were elevated compared to values of healthy persons. At 4 h after trauma, TNFalpha and sTNF-R2 showed an increase from initial values, which continued during the entire observation period. Severe trauma led to enhanced sTNF-R1 levels on scene and on hospital admission. Development of SIRS along with elevated sTNF-R1 began on scene and was present on admission, with increased sTNF-R2 from day 1 to day 4. MODS (until day 6) was preceded by increased sTNF-R2 levels on admission and up to 4 h after trauma. Outcome was associated neither with TNFalpha nor with soluble TNF receptor levels. Thus, in trauma patients, early post-traumatic MODS and SIRS coincide with increased levels of TNFalpha and TNF receptor proteins, revealing different, time-dependent changes. Hence, detection of TNFalpha and soluble TNF receptor proteins after trauma should pay regard to the time point of sampling.

Post-traumatic multiple organ dysfunction syndrome — infection is an uncommon antecedent risk factor

A pattern of multiple organ dysfunction syndrome (MODS) and risk factors following blunt trauma was identified, based on analyses of clinical data from 3611 patients who were admitted directly to a level I trauma centre and had hospital stays ≥3 days. Five system dysfunctions were simultaneously associated ( P<0.05) with death (adjusted odds ratio): adult respiratory distress syndrome (ARDS) (4.9), renal failure (6.7), hyperglycaemia (3.6), recurrent acidosis (4.8) and hypoalbuminaemia (1.8). Mortality increased with the number of system dysfunctions. For the 336 patients with MODS (≥2 dysfunctions), mortality was 32.4 per cent compared with 1.3 per cent in the non-MODS group ( P = 0.0001). Of the 254 with MODS occurring within 72 hours, mortality was 27 per cent compared with 49 per cent in those manifesting MODS later ( P < 0.001). The 175 (52.1 per cent) with organ failure (renal failure and/or ARDS) also had metabolic dysfunction. Seven admission risk factors were independently associated ( P < 0.003) with MODS [adjusted odds ratio]: pre-existing condition (3.4), age > 50 (3.1). Injury Severity Score ≥25 (6.4), hypotension (2.8), acidaemia (2.2), 24 h blood loss > 1l (3.7), and major base deficit (1.6). Only 13 per cent with MODS had an infection in the 5 days before or at initiation of MODS. Haemodynamic instability, acidosis, blood loss, pre-existing condition, age and serious injury were risk factors independently related to life-threatening MODS, but infection was an uncommon precursor except in late MODS. These risk factors may predict which blunt trauma patients will require costly resources or are appropriate for investigation studies.