Venous thrombosis (VT), a leading cause of morbidity and mortality worldwide, has recently been linked to neutrophil activation and release of neutrophil extracellular traps (NETs) via a process ...called NETosis. The use of various in vivo thrombosis models and genetically modified mice has more precisely defined the exact role of NETosis in the pathogenesis of VT. Translational large animal VT models and human studies have confirmed the presence of NETs in pathologic VT. Activation of neutrophils, with subsequent NETosis, has also been linked to acute infection. This innate immune response, while effective for bacterial clearance from the host by formation of an intravascular bactericidal "net," also triggers thrombosis. Intravascular thrombosis related to such innate immune mechanisms has been coined immunothrombosis. Dysregulated immunothrombosis has been proposed as a mechanism of pathologic micro- and macrovascular thrombosis in sepsis and autoimmune disease. In this focused review, we will address the dual role of NETs in the pathogenesis of VT and immunothrombosis.
IMPORTANCE: Appropriate risk stratification for venous thromboembolism (VTE) is essential to providing appropriate thromboprophylaxis and avoiding morbidity and mortality. OBJECTIVE: To validate the ...Caprini VTE risk assessment model in a previously unstudied high-risk cohort: critically ill surgical patients. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study of 4844 adults (≥18 years old) admitted to a 20-bed surgical intensive care unit in a large tertiary care academic hospital during a 5-year period (July 1, 2007, through June 30, 2012). MAIN OUTCOMES AND MEASURES: The main study outcome was VTE (defined as patients with deep vein thrombosis or pulmonary embolism) that occurred during the patient’s initial hospital admission. RESULTS: The study population was distributed among risk levels as follows: low, 5.3%; moderate, 19.9%; high, 31.6%; highest, 25.4%; and superhigh, 14.9%. The overall incidence of inpatient VTE was 7.5% and increased with risk level: 3.5% in low-risk patients, 5.5% in moderate-risk patients, 6.6% in high-risk patients, 8.6% in highest-risk patients, and 11.5% in superhigh-risk patients. Patients with Caprini scores greater than 8 were significantly more likely to develop inpatient VTE events when compared with patients with Caprini scores of 7 to 8 (odds ratio OR, 1.37; 95% CI, 1.02-1.85; P = .04), 5 to 6 (OR, 1.35; 95% CI, 1.16-1.57; P < .001), 3 to 4 (OR, 1.30; 95% CI, 1.16-1.47; P < .001), or 0 to 2 (OR, 1.37; 95% CI, 1.16-1.64; P < .001). Similarly, patients with Caprini scores of 7 to 8 were significantly more likely to develop inpatient VTE when compared with patients with Caprini scores of 5 to 6 (OR, 1.33; 95% CI, 1.01-1.75; P = .04), 3 to 4 (OR, 1.27; 95% CI, 1.08-1.51; P = .005), or 0 to 2 (OR, 1.38; 95% CI, 1.10-1.74; P = .006). CONCLUSIONS AND RELEVANCE: The Caprini VTE risk assessment model is valid. This study supports the use of individual risk assessment in critically ill surgical patients.
Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is ...driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.
Deep vein thrombosis and pulmonary embolism are a significant health care concern, representing a major source of mortality and morbidity. In order to understand the pathophysiology of thrombogenesis ...and thrombus resolution, animal models are necessary. Mouse models of venous thrombosis contribute to our understanding of the initiation, propagation, and resolution of venous thrombus, as well as allow for the evaluation of new pharmaceutical approaches to prophylaxis and treatment of deep vein thrombosis. In this work we review the ferric chloride model, the inferior vena cava ligation model, the inferior vena cava stenosis models, and the electrolytic inferior vena cava model and compare their advantages and disadvantages.
Macrophages play a critical role in the establishment of a regulated inflammatory response following tissue injury. Following injury, CCR2+ monocytes are recruited from peripheral blood to wound ...tissue, and direct the initiation and resolution of inflammation that is essential for tissue repair. In pathologic states where chronic inflammation prevents healing, macrophages fail to transition to a reparative phenotype. Using a murine model of cutaneous wound healing, we found that CCR2‐deficient mice (CCR2−/−) demonstrate significantly impaired wound healing at all time points postinjury. Flow cytometry analysis of wounds from CCR2−/− and WT mice revealed a significant decrease in inflammatory, Ly6CHi recruited monocyte/macrophages in CCR2−/− wounds. We further show that wound macrophage inflammatory cytokine production is decreased in CCR2−/− wounds. Adoptive transfer of mT/mG monocyte/macrophages into CCR2+/+ and CCR2−/− mice demonstrated that labeled cells on days 2 and 4 traveled to wounds in both CCR2+/+ and CCR2−/− mice. Further, adoptive transfer of monocyte/macrophages from WT mice restored normal healing, likely through a restored inflammatory response in the CCR2‐deficient mice. Taken together, these data suggest that CCR2 plays a critical role in the recruitment and inflammatory response following injury, and that wound repair may be therapeutically manipulated through modulation of CCR2.
Upon initial tissue injury, CCL2, one of the primary ligands for CCR2, is increased in the wound. This ligand binds the CCR2 receptors that are present on Ly6CHi monocytes, recruiting these cells to the wound, allowing initiation of the macrophage‐mediated inflammatory phase of wound healing.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
OBJECTIVE:Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired ...inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined.
APPROACH AND RESULTS:Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3−, CD19−, Ly6G−) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow–derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL interleukin-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow–derived macrophages and wound macrophages. This demonstrated decreased expression of Mll1, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow–derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in MLL1 compared with nonseptic controls.
CONCLUSIONS:These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1–mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and ...inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (
< 0.05), and increased THP-1 monocyte adhesion to ECs (
= 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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