The roles of tissue-resident macrophages in sepsis-associated organ dysfunction.

Sepsis, a syndrome caused by a dysregulated host response to infection and characterized by life-threatening organ dysfunction, particularly septic shock and sepsis-associated organ dysfunction (SAOD), is a medical emergency associated with high morbidity, high mortality, and long-term sequelae. Tissue-resident macrophages (TRMs) are a subpopulation of macrophages derived primarily from yolk sac progenitors and fetal liver during embryogenesis, located primarily in non-lymphoid tissues in adulthood, capable of local self-renewal independent of hematopoiesis, and developmentally and functionally restricted to the non-lymphoid organs in which they reside. TRMs are the first line of defense against life-threatening conditions such as sepsis, tumor growth, traumatic-associated organ injury, and surgical-associated injury. In the context of sepsis, TRMs can be considered as angels or demons involved in organ injury. Our proposal is that sepsis, septic shock, and SAOD can be attenuated by modulating TRMs in different organs. This review summarizes the pathophysiological mechanisms of TRMs in different organs or tissues involved in the development and progression of sepsis.

Factors affecting do-not-attempt-resuscitation (DNAR) decisions among adult patients in the emergency department of a general tertiary teaching hospital in China: a retrospective observational study.

OBJECTIVE: Do-not-attempt-resuscitation (DNAR) orders are designed to allow patients to opt out of receiving cardiopulmonary resuscitation in the event of a cardiac arrest. While DNAR has become a standard component of medical care, there is limited research available specifically focusing on DNAR orders in the context of emergency departments in China. This study aimed to fill that gap by examining the factors related to DNAR orders among patients in the emergency department of a general tertiary teaching hospital in China. DESIGN: Retrospective observational study. SETTING: Emergency department. PARTICIPANTS: This study and analysis on adult patients with DNAR or no DNAR data between 1 January 2022 and 1 January 2023 in the emergency department of a large academic comprehensive tertiary teaching hospital. A total of 689 were included in our study. PRIMARY OUTCOME MEASURES: Whether the patient received DNAR was our dependent variable. RESULTS: Among the total patients, 365 individuals (53.0%) had DNAR orders. The following variables, including age, sex, age-adjusted Charlson comorbidity index (ACCI), primary diagnosis of cardiogenic or cancer related, history of neurological dysfunction or cancer, were independently associated with the difference between the DNAR group and the no DNAR group. Furthermore, there were significant statistical differences observed in the choice of DNAR among patients with different stages of cancer. CONCLUSIONS: In comparison to the no DNAR group, patients with DNAR were characterised by being older, having a higher proportion of female patients, higher ACCI scores, a lower number of patients with a primary diagnosis of cardiogenic and a higher number of patients with a primary diagnosis of cancer related, history of neurological dysfunction or cancer.

Severe Hypokalemia Complicated by Acute Myopathy: Initial Manifestation of Primary Sjögren's Syndrome-Associated Renal Tubular Acidosis.

BACKGROUND Severe hypokalemia, which often causes life-threatening malignant arrhythmias, is usually first diagnosed in the Emergency Department (ED). It is important to note that hypokalemia is often closely and complexly related to renal tubular acidosis (RTA) associated with autoimmune diseases such as Sjögren's syndrome (SS), especially in females with acute myopathy or acute liver injury (ALI). Severe hypokalemia can directly cause muscle injury, which can lead to hyper-creatine kinaseemia (HCK) and ALI, while SS can also directly cause hypokalemia, HCK, and even ALI and renal tubular/interstitial injury. Therefore, by reporting a rare case of SS-associated RTA (SS-RTA), we systematically reviewed the relationship between SS-RTA and severe hypokalemia, which may be beneficial to increase attention on this topic. CASE REPORT A 35-year-old female patient who presented to the ED primarily for limb weakness symptoms was initially diagnosed with severe hypokalemia, acute myopathy, and ALI. She was eventually diagnosed with primary SS (pSS) and SS-RTA, although she did not present with the typical dry mouth, dry eyes, and other clinical manifestations of SS. CONCLUSIONS Severe hypokalemia is a serious life-threatening emergency, and although the differential diagnosis is very broad, we should be aware of RTA associated with autoimmune diseases such as SS in female patients, especially when combined with clinical manifestations such as acute myopathy and ALI that cannot be explained by other causes. Simultaneously, we hope to be able to guide emergency physicians encountering similar patients to complete the diagnostic and therapeutic process.

A 30-Year-Old Woman with a History of Autoimmune Hyperthyroidism Presenting with Fever and Oral Ulcers, Diagnosed with Discoid Lupus Erythematosus.

BACKGROUND Lupus erythematosus (LE) is mainly clinically divided into cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) depending on the presence of multi-system manifestations. The most common subtype of CLE is discoid lupus erythematosus (DLE). Graves' disease (GD) is immunologically characterized by lymphocytic infiltration of the thyroid gland and the presence of thyroid-stimulating hormone (TSH) receptor antibodies (TSH-R-Ab), and is the most common autoimmune pathogenic cause of hyperthyroidism. Autoimmune thyroid dysfunction has been widely described in association with rheumatic diseases. A certain rate of coexistence of GD with LE, mainly SLE, has been reported in the literature. Herein, we present a rare case of Graves' hyperthyroidism complicated with DLE. CASE REPORT A 30-year-old female patient, with a history of hyperthyroidism and discontinued methimazole treatment, initially presented with symptoms of infection and oral ulcers. Thyroid hormone, thyroid-stimulating hormone receptor antibody, and immunological tests were consistent with a diagnosis of Graves' hyperthyroidism-associated DLE. Corticosteroids and radioactive iodine (RAI) were used to treat DLE and GD, respectively. Post-treatment evaluation suggested the remission of her hyperthyroidism and active DLE. CONCLUSIONS Autoimmune thyroid diseases have been previously described in association with rheumatic diseases. This association shows the importance of prompt awareness of the increased risk of DLE when evaluating autoimmune thyroid dysfunction, especially under certain conditions, such as after treatment with anti-thyroid drugs (ATDs), or in the absence of multiple organ damage manifestations of SLE.

Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling.

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.

Rutin Inhibits Cardiac Apoptosis and Prevents Sepsis-Induced Cardiomyopathy.

Rutin is a flavanol-type polyphenol that consists of flavanol quercetin and the disaccharide rutinose, which has been reported to exert various biological effects such as antioxidant and anti-inflammatory activities. It is not clear whether rutin has a protective effect on sepsis-induced cardiomyopathy (SIC). In this study, we used male C57BL/6 mice and cecal ligation and puncture (CLP) surgery to establish the model of SIC. Rutin was precautionarily treated (50, 100, 200 mg/kg per day, 7 days) before CLP. The results showed that rutin pretreatment (100, 200 mg/kg per day, 7 days) reduced the mortality of murine sepsis. We chose the 100 mg/kg dose for further studies. Mice were pretreatment with rutin (100 mg/kg per day, 7 days) before subjected to CLP, and myocardial tissue and blood samples were collected 24 h after CLP. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cTNT decreased, while interleukin-10 (IL-10) increased with rutin pretreatment. The cardiomyocytes apoptosis and mitochondrial dysfunction were also alleviated with rutin pretreatment. In conclusion, this study confirmed the efficacy of rutin-enriched diet in the prophylaxis of cardiac apoptosis and cardiac injury induced by CLP in mouse model. It provides a potential new approach on SIC prophylaxis in sepsis.

The roles of macrophage polarization in the host immune response to sepsis.

Sepsis is a life-threatening clinical syndrome caused by infection. Its pathogenesis is complex and entails coagulation dysfunction, inflammation, and immune disorders. Macrophages are important components of innate and adaptive immunity that are highly heterogeneous and plastic. They can polarize into a multi-dimensional spectrum of phenotypes with different functions relating to immune regulation in response to changes in the microenvironment of specific tissues. We reviewed studies that examined the role of macrophage polarization with a focus on the classical activated (M1-like) and alternative activated (M2-like) macrophages as the two main phenotypes involved in the host immune response to sepsis. A complex regulatory network is involved in the process of macrophage polarization, which is influenced by a variety of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. M1-like macrophages release large quantities of pro-inflammatory mediators, while M2-like macrophages release large quantities of anti-inflammatory mediators. An imbalance between M1-like and M2-like macrophages induces the occurrence and development of sepsis. Therefore, targeted regulation of the process of macrophage polarization could be a useful approach to normalize the immune balance of the host, offering a new treatment modality for different stages of sepsis.

Acute pericardial tamponade: The initial manifestation of systemic lupus erythematosus with Graves' hyperthyroidism.

Acute pericardial tamponade, which can cause obstructive shock, is a serious life-threatening medical emergency that can be readily reversed by timely identification and appropriate intervention. Acute pericardial tamponade can occur for a number of reasons, including idiopathic, malignancy, uremia, iatrogenic, post-myocardial infarction, infection, collagen vascular, hypothyroidism, and others. Systemic lupus erythematosus (SLE) and hyperthyroidism associated with pericardial tamponade are rarely reported. Here, we report the case of a 20-year-old female patient was final diagnosed of SLE with Graves' hyperthyroidism.

Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury.

Histones are considered potential risk factors that contribute to the development of septic acute kidney injury (SAKI) by inducing apoptosis and inflammation. This study aimed to explore the protective effects of heparin on septic acute kidney injury through the neutralization of extracellular histones (EH) and to uncover the underlying mechanism. C57BL mice (16 each) were randomly divided into the sham group, the sepsis group (established by cecal ligation and puncture operation, CLP), and the heparin intervention group. Mice in the heparin intervention group received a subcutaneous injection of unfractionated heparin (0.03 IU/g) 4 h after CLP. At 6 h after the operation, nine mice from each group were sacrificed by the removal of the eyeballs to harvest blood samples; the upper half of the right kidney was used as the study sample. Mice renal tubular epithelial cells cultivated in six-well plates were equally divided into five groups. We cultured cells treated with either histone (40 U), histone (40 U) + heparin (25 IU/ml), histone(40U) + lipopolysaccharides (LPS; 10 µg/ml), or histone (40 U) + LPS (10 µg/ml) + heparin (25 IU/ml) for 6 h. For the histone + heparin group and the histone + LPS + heparin group, histone (and LPS) were treated with heparin simultaneously. Mice in the heparin intervention group showed decreased levels of EH4, neutrophil gelatinase-associated lipocalin (NAGL), kidney injury molecule-1 (KIM-1), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 in the blood serum, longer average 72-h survival rate, significantly decreased kidney tissue edema, and a clearer glomerular structure coupled with decreased protein and mRNA expression levels of kidney apoptosis-related proteins (cleaved Caspase-3/Caspase-3 and Bax/Bcl-2) compared with those in the sepsis group at 6 h after CLP (P < 0.05). Meanwhile, cells in the heparin intervention group exhibited lower expression levels of serum EH4 and inflammatory cytokines, a lower apoptosis rate, and decreased expression of apoptosis-related proteins, both at protein and mRNA levels, than those in the histone-stimulated group at 6 h after stimulation (P < 0.05). Heparin may alleviate apoptosis and inflammation through the neutralization of histones, thus playing a protective role against septic acute kidney injury.

Quick Sequential Organ Failure Assessment as a prognostic factor for infected patients outside the intensive care unit: a systematic review and meta-analysis.

Quick Sequential Organ Failure Assessment (qSOFA) was proposed to replace SIRS as a new screening tool for the identification of septic patients at high mortality. However, researches from infected patients outside of ICU especially in Emergency Department (ED) drew contradictory conclusions on the prognostic value of qSOFA. This systematic review evaluated qSOFA as a prognostic marker of infected patients outside of ICU. The primary outcome was hospital mortality or 28- or 30-day mortality. Data were pooled based on sensitivity and specificity. Twenty-four trials with 121,237 participants were included. qSOFA had a poor sensitivity (0.58 [95% CI 0.47-0.67], 0.54 [95% CI 0.43-0.65]) and moderate specificity (0.69 [95% CI 0.48-0.84], 0.77 [95% CI 0.66-0.86]) for prediction of mortality in patients outside of ICU and ED patients only. Studies that used in-hospital mortality showed a higher sensitivity (0.61 [95% CI 0.50-0.71] vs 0.32 [95% CI 0.15-0.49]) and lower specificity (0.70 [95% CI 0.59-0.82] vs 0.92 [95% CI 0.85-0.99]) than studies that used 28 or 30-day mortality. Studies with overall mortality < 10% showed higher specificity (0.89 [95% CI 0.82-0.95] vs 0.62 [95% CI 0.48-0.76]) than studies with overall mortality ≥ 10%. There is no difference in the accuracy of diagnosis of sepsis between positive qSOFA scores and SIRS criteria. qSOFA was poor sensitivity and moderate specificity in predicting mortality of infected patients outside of ICU especially in ED. Combining qSOFA and SIRS may be helpful in predicting mortality.

Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis.

Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words "pyro" and "ptosis" in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain-containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis.

TOB1 Deficiency Enhances the Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Tendon-Bone Healing in a Rat Rotator Cuff Repair Model.

BACKGROUND/AIMS: This study investigated the effect of silencing TOB1 (Transducer of ERBB2, 1) expression in bone marrow-derived mesenchymal stem cells (MSCs) on MSC-facilitated tendon-bone healing in a rat supraspinatus repair model. METHODS: Rat MSCs were transduced with a recombinant lentivirus encoding short hairpin RNA (shRNA) against TOB1. MSC cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The effect of MSCs with TOB1 deficiency on tendon-bone healing in a rat rotator cuff repair model was evaluated by biomechanical testing, histological analysis and collagen type I and II gene expression. An upstream regulator (miR-218) of TOB1 was determined in MSCs. RESULTS: We found that knockdown of TOB1 significantly increased the proliferative activity of rat MSCs in vitro. When MSCs with TOB1 deficiency were injected into injured rat supraspinatus tendon-bone junctions, the effect on tendon-bone healing was enhanced compared to treatment with control MSCs with normal TOB1 expression, as evidenced by elevated levels of ultimate load to failure and stiffness, increased amount of fibrocartilage and augmented expression of collagen type I and type II genes. In addition, we found that the TOB1 3' untranslated region is a direct target of miR-218. Similar to the effect of TOB1 deficiency, overexpression of miR-218 effectively promoted tendon-bone healing in rat. CONCLUSION: These results suggest that TOB1 may play a negative role in the effect of MSCs on tendon-bone healing, and imply that expression of TOB1 may be regulated by miR-218.