Neutrophil extracellular trap (NET) formation is a hallmark of many disorders that involve neutrophil recruitment, tissue damage, and inflammation. As NET formation is often associated with ...neutrophil death, the term “NETosis” has become popular. Upon discovery that neutrophils may survive NET release, apparent misnomers, such as “vital NETosis,” have been proposed. Meanwhile, it has become obvious that certain stimuli can trigger neutrophil necroptosis, a process associated with NET-like chromatin release. Here, we discuss the relationship between NET release and neutrophil death in view highlighting that many assays used in the field do not properly distinguish between the two. An updated nomenclature is needed replacing the term “NETosis” to meet the growing variety of settings leading to chromatin release with and without neutrophil death. Dissecting which triggers of NET release involve which signaling pathway will help to define drugable molecular targets that inhibit NET release and/or neutrophil necrosis in specific disorders.
Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that ...may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosis
, histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils.
, ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure.
Crystals and nano‐ and microparticles form inside the human body from intrinsic proteins, minerals, or metabolites or enter the body as particulate matter from occupational and environmental sources. ...Associated tissue injuries and diseases mostly develop from cellular responses to such crystal deposits and include inflammation, cell necrosis, granuloma formation, tissue fibrosis, and stone‐related obstruction of excretory organs. But how do crystals and nano‐ and microparticles trigger these biological processes? Which pathomechanisms are identical across different particle types, sizes, and shapes? In addition, which mechanisms are specific to the atomic or molecular structure of crystals or to specific sizes or shapes? Do specific cellular or molecular mechanisms qualify as target for therapeutic interventions? Here, we provide a guide to approach this diverse and multidisciplinary research domain. We give an overview about the clinical spectrum of crystallopathies, about shared and specific pathomechanisms as a conceptual overview before digging deeper into the specialty field of interest.
Crystals and nano‐ and microparticles form inside the human body from intrinsic proteins, minerals, or metabolites or enter the body as particulate matter from occupational and environmental sources. Associated tissue injuries and diseases mostly develop from cellular responses to crystal deposits and include inflammation, cell necrosis, granuloma formation, tissue fibrosis, and stone‐related obstruction of excretory organs. We give an overview about the clinical spectrum of crystallopathies.
Cholesterol crystal (CC) embolism is a complication of advanced atherosclerotic plaques located in the major arteries. This pathological condition is primarily induced by interventional and surgical ...procedures or occurs spontaneously. CC can induce a wide range of tissue injuries including CC embolism syndrome, a spontaneous or intervention‐induced complication of advanced atherosclerosis, while treatment of CC embolism has remained empiric. Vascular occlusions caused by CC embolism may exceed the ischemia tolerance of many tissues, particularly when small arteries are affected. The main approach to CC embolism is primary prophylaxis in patients at risk by stabilizing atherosclerotic plaques and avoiding unnecessary catheter interventions. During CC embolism, the use of platelet inhibitors to avoid abnormal activation and aggregation and anticoagulants may reduce the risk of vascular occlusions and tissue ischemia. This probably explains the relatively low prevalence of clinical manifestations of CC embolism, which are frequently found in autopsy studies. In this review, we summarized the current knowledge on the pathophysiology of CC embolism syndrome deriving from clinical observations and experimental mouse models. Furthermore, we described the risk factors of CC embolism in humans as well as the experimental studies based on empiric treatments. We also discuss potential therapeutic interventions based on recent experimental data and emerging drug options evolving from other research domains. Given the substantial unmet medical need to improve the outcomes of CC embolism, the identification of effective treatment strategies is urgently needed.
Cholesterol crystal (CC) embolism is a complication of advanced atherosclerotic plaques. It is primarily induced by anticoagulants and thrombolytic interventions and vascular surgical procedures. The main approach to CC embolism is primary prophylaxis in patients at risk by stabilizing atherosclerotic plaques (statin therapy) and avoiding unnecessary catheter interventions. Platelet aggregation inhibitors and anticoagulants may reduce the risk of vascular occlusions in case CC embolism occurs. Furthermore, life style controlling is another useful way to prevent atherosclerosis and CC embolism.
Although the prognosis of lupus nephritis (LN) has improved over the last few decades, 5–20% of patients still progress to kidney failure. Hence, there is an unmet need to improve the management of ...LN. Two novel drugs, belimumab and voclosporin, have been recently approved for LN and obinutuzumab is in the late stage of development. In randomised controlled trials (RCTs), all these drugs, added to the standard-of-care, were more effective than standard-of-care alone in achieving renal response. Now the question is: should these new drugs be used early in the disease course or just in refractory patients? The main reasons supporting the early use are based on the RCTs that demonstrated benefits when combinatory regimen was initiated early in incident and relapsing patients leading to a higher proportion of patients to achieve renal response, hence reducing nephron loss and the risk of kidney failure. The main reasons supporting the use of the combinatory regimens primarily in relapsing/refractory patients acknowledge that many patients responded well even without add-on medications, allowing a more economic use of innovative and costly drugs. However, good predictors of renal response to standard-of-care are lacking and, thus, the decision of adding new treatments early or just in refractory or relapsing patients has to consider drug access, risks of over or undertreatment, and preservation of kidney function in high-risk individuals.
•Despite the improvement of LN prognosis in the last few decades, 5–20% of patients affected with LN still progress to kidney failure.•Belimumab and voclosporin, used on the top of standard of care (SoC), have been recently approved for the treatment of LN.•In RCTs, a higher proportion of patients treated with the combinatory regimens achieved renal response, which is known to protect from nephron loss and kidney failure.•Good predictors of renal response to SoC are lacking and, thus, it remains difficult to define those patients that will or will not benefit from combination therapies.•The use of the combinatory regimens should be based on drug access, risks of over or undertreatment, and preservation of kidney function in high-risk individuals.
Primary/secondary hyperoxalurias involve nephrocalcinosis-related chronic kidney disease (CKD) leading to end-stage kidney disease. Mechanistically, intrarenal calcium oxalate crystal deposition is ...thought to elicit inflammation, tubular injury and atrophy, involving the NLRP3 inflammasome. Here, we found that mice deficient in NLRP3 and ASC adaptor protein failed to develop nephrocalcinosis, compromising conclusions on nephrocalcinosis-related CKD. In contrast, hyperoxaluric wild-type mice developed profound nephrocalcinosis. NLRP3 inhibition using the β-hydroxybutyrate precursor 1,3-butanediol protected such mice from nephrocalcinosis-related CKD. Interestingly, the IL-1 inhibitor anakinra had no such effect, suggesting IL-1-independent functions of NLRP3. NLRP3 inhibition using 1,3-butanediol treatment induced a shift of infiltrating renal macrophages from pro-inflammatory (CD45+F4/80+CD11b+CX3CR1+CD206-) and pro-fibrotic (CD45+F4/80+CD11b+CX3CR1+CD206+TGFβ+) to an anti-inflammatory (CD45+F4/80+CD11b+CD206+TGFβ-) phenotype, and prevented renal fibrosis. Finally, in vitro studies with primary murine fibroblasts confirmed the non-redundant role of NLRP3 in the TGF-β signaling pathway for fibroblast activation and proliferation independent of the NLRP3 inflammasome complex formation. Thus, nephrocalcinosis-related CKD involves NLRP3 but not necessarily via intrarenal IL-1 release but rather via other biological functions including TGFR signaling and macrophage polarization. Hence, NLRP3 may be a promising therapeutic target in hyperoxaluria and nephrocalcinosis.
From kidney injury to kidney cancer Peired, Anna Julie; Lazzeri, Elena; Guzzi, Francesco ...
Kidney international,
07/2021, Letnik:
100, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is ...unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer).
Although platelets are critically involved in thrombosis and hemostasis, experimental and clinical evidence indicate that platelets promote tumor progression and metastasis through a wide range of ...physical and functional interactions between platelets and cancer cells. Thrombotic and thromboembolic events are frequent complications in patients with solid tumors. Hence, cancer modulates platelet function by directly inducing platelet-tumor aggregates and triggering platelet granule release and altering platelet turnover. Also, platelets enhance tumor cell dissemination by activating endothelial cell function and recruiting immune cells to primary and metastatic tumor sites. In this review, we summarize current knowledge on the complex interactions between platelets and tumor cells and the host microenvironment. We also critically discuss the potential of anti-platelet agents for cancer prevention and treatment.
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